Inhibitor compounds

ABSTRACT

The present invention relates to compounds of formula I 
                         
wherein R 1 , R 4 , Ar, W, X and Z are all as defined herein. The compounds of the present invention are known to inhibit the spindle checkpoint function of Monospindle 1 (Mps1—also known as TTK) kinases either directly or indirectly via interaction with the Mps1 kinase itself. In particular, the present invention relates to the use of these compounds as therapeutic agents for the treatment and/or prevention of proliferative diseases, such as cancer. The present invention also relates to processes for the preparation of these compounds, and to pharmaceutical compositions comprising them.

RELATED APPLICATIONS

This application is a Continuation Application of U.S. patentapplication Ser. No. 14/426,549 filed Mar. 6, 2015, which is the U.S.National Stage of International Patent Application No.PCT/GB2013/052360, filed Sep. 9, 2013, which claims the benefit ofpriority to Great Britain Patent Application serial number 1216017.2,filed Sep. 7, 2012, the entire contents of each of which are expresslyincorporated by reference in their entirety.

INTRODUCTION

The present invention relates to compounds that inhibit the spindlecheckpoint function of monopolar spindle 1 (Mps1—also known as TTK)kinases, either directly or indirectly via interaction with the Mps1kinase itself. In particular, the present invention relates to compoundsfor use as therapeutic agents for the treatment and/or prevention ofproliferative diseases, such as cancer. The present invention alsorelates to processes for the preparation of these compounds, and topharmaceutical compositions comprising them.

BACKGROUND OF THE INVENTION

Cancer is caused by uncontrolled and unregulated cellular proliferation.Precisely what causes a cell to become malignant and proliferate in anuncontrolled and unregulated manner has been the focus of intenseresearch over recent decades. This research has led to the targeting ofsurveillance mechanisms, such as those responsible for regulating thecell cycle, with anticancer agents. For example, published patentapplication WO 2009/103966 (CANCER RESEARCH TECHNOLOGY LIMITED) relatesto the inhibition of checkpoint kinase 1 (CHK1) kinase function, withbicyclylaryl-aryl-amine compounds, in the treatment of cancer.

The main role of the cell cycle is to enable error-free DNA replication,chromosome segregation and cytokinesis. Surveillance mechanisms, theso-called checkpoint pathways, monitor passage through mitosis atseveral stages. One of the best characterised is the spindle assemblycheckpoint that prevents anaphase onset until the appropriate tensionand attachment across kinetochores is achieved (HARDWICK K G, 1998, “Thespindle checkpoint”, Trends Genet 14, 1-4). The majority of proteinsinvolved in the checkpoint exert their functions through protein bindinginteractions with the involvement of only a small number of kinases(MUSACCHIO A et al, 2007, “The spindle-assembly checkpoint in space andtime”, Nature Reviews, Molecular and Cell Biology, 8, 379-393). Amitotic checkpoint complex (MCC) that contains three checkpoint proteins(Mad2, BubR1/Mad3, Bub3) and the APC/C co-factor, CDC20, concentrates atthe kinetochores and acts as a spindle checkpoint effector. Other coreproteins required to amplify the checkpoint signal include Mad1 and thekinases Bub1, Mps1 (also known as TTK) and Aurora-B (MUSACCHIO,referenced above).

One of the first components of the spindle assembly checkpoint signal,identified by a genetic screen in budding yeast, was dubbed Mps1(monopolar spindle 1) for the monopolar spindles produced by Mps1 mutantcells (WEISS E, 1996, “The Saccharomyces cerevisiae spindle pole bodyduplication gene MPS1 is part of a mitotic checkpoint”, J Cell Biol 132,111-123), however, it still remains one of the least studied checkpointcomponents in higher eukaryotes. Subsequently, the Mps1 gene was shownto encode an essential dual-specificity kinase (LAUZE et al, 1995,“Yeast spindle pole body duplication gene MPS1 encodes an essential dualspecificity protein kinase”, EMBO J 14, 1655-1663 and also POCH et al,1994, “RPK1, an essential yeast protein kinase involved in theregulation of the onset of mitosis, shows homology to mammaliandual-specificity kinases”, Mol Gen Genet 243, 641-653) conserved fromyeast to humans (MILLS et al, 1992, “Expression of TTK, a novel humanprotein kinase, is associated with cell proliferation”, J Biol Chem 267,16000-16006). Mps1 activity peaks at the G₂/M transition and is enhancedupon activation of the spindle checkpoint with nocodazole (STUCKE et al,2002, “Human Mps1 kinase is required for the spindle assembly checkpointbut not for centrosome duplication”, EMBO J 21, 1723-1732 and also LIUet al, 2003, “Human MPS1 kinase is required for mitotic arrest inducedby the loss of CENP-E from kinetochores”, Mol Biol Cell 14, 1638-1651).The autophosphorylation of Mps1 at Thr676 in the activation loop hasbeen identified and is essential for Mps1 function (MATTISON et al,2007, “Mps1 activation loop autophosphorylation enhances kinaseactivity”, J Biol Chem 282, 30553-30561).

Given the importance of Mps1 in spindle checkpoint activation, thedevelopment of Mps1 inhibitors would be an asset, not only as a tool tofurther investigate its cell cycle-related functions, but also as a formof anticancer treatment. The first generation inhibitors of Mps1 havebeen described. Cincreasin, caused chromosome mis-segregation and deathin yeast cells (DORER et al, 2005, “A small-molecule inhibitor of Mps1blocks the spindle-checkpoint response to a lack of tension on mitoticchromosomes”, Curr Biol 15, 1070-1076) and SP600125, a JNK (c-Junamino-terminal kinase) inhibitor, also disrupts spindle checkpointfunction in a JNK-independent manner via the inhibition of Mps1 (SCHMIDTet al, 2005, “Ablation of the spindle assembly checkpoint by a compoundtargeting Mps1”, EMBO Rep 6, 866-872). Recently, three small moleculeinhibitors of Mps1 were identified (KWIATOWSKI et al, 2010,“Small-molecule kinase inhibitors provide insight into Mps1 cell cyclefunction”, Nat Chem Biol 6, 359-368; HEWITT et al, 2010, “Sustained Mps1activity is required in mitosis to recruit O-Mad2 to the Mad1-C-Mad2core complex”, J Cell Biol 190, 25-34; and SANTAGUIDA et al, 2010,“Dissecting the role of MPS1 in chromosome biorientation and the spindlecheckpoint through the small molecule inhibitor reversine”, J Cell Biol190, 73-87). Chemical inhibition of Mps1 induced premature mitotic exit,gross aneuploidy and death to human cancer cell lines (KWIATOWSKI,above). Mps1 inhibitors AZ3146 and reversine, severely impairedrecruitment of Mad1, Mad2 and CENP-E to kinetochores (HEWITT, andSANTAGUIDA, above).

Dysregulation of the mitotic checkpoint is recognised as a feature ofthe malignant transformation process. Mitotic checkpoint dysfunction intumors provides an opportunity for developing a therapeutic strategyusing small molecules. This is based on the proposition thatpharmacologic disruption of an already compromised mitotic checkpointmay selectively sensitize tumors. This observation has led to thehypothesis that inhibition of Mps1 may be of therapeutic benefit.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound, or apharmaceutically acceptable salt or solvate thereof, as defined herein.

In another aspect, the present invention provides a pharmaceuticalcomposition which comprises a compound as defined herein, or apharmaceutically acceptable salt or solvate thereof, and one or morepharmaceutically acceptable excipients.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein for use in therapy.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein, for use in the treatmentof a proliferative condition.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein, for use in the treatmentof cancer. In a particular embodiment, the cancer is a human cancer.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein, for use in the productionof a Mps1 kinase inhibitory effect.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt or solvatethereof, in the manufacture of a medicament for use in the treatment ofa proliferative condition.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt or solvatethereof, in the manufacture of a medicament for use in the treatment ofcancer. Suitably, the medicament is for use in the treatment of humancancers.

In another aspect, the present invention provides the use of a compoundas defined herein, or a pharmaceutically acceptable salt or solvatethereof, in the manufacture of a medicament for use in the production ofan Mps1 kinase inhibitory effect.

In another aspect, the present invention provides a method of inhibitingMps1 kinase in vitro or in vivo, said method comprising contacting acell with an effective amount of a compound as defined herein, or apharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of inhibitingcell proliferation in vitro or in vivo, said method comprisingcontacting a cell with an effective amount of a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a method of treating aproliferative disorder in a patient in need of such treatment, saidmethod comprising administering to said patient a therapeuticallyeffective amount of a compound as defined herein, or a pharmaceuticallyacceptable salt or solvate thereof, or a pharmaceutical composition asdefined herein.

In another aspect, the present invention provides a method of treatingcancer in a patient in need of such treatment, said method comprisingadministering to said patient a therapeutically effective amount of acompound as defined herein, or a pharmaceutically acceptable salt orsolvate thereof, or a pharmaceutical composition as defined herein.

The present invention further provides a method of synthesising acompound as defined herein, or a pharmaceutically acceptable salt orsolvate thereof.

In another aspect, the present invention provides a compound as definedherein, or a pharmaceutically acceptable salt or solvate thereof,obtainable by, or obtained by, or directly obtained by a method ofsynthesis as defined herein.

In another aspect, the present invention provides novel intermediatesdefined herein which are suitable for use in any one of the syntheticmethods set out herein.

Preferred, suitable, and optional features of any one particular aspectof the present invention are also preferred, suitable, and optionalfeatures of any other aspect.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Unless otherwise stated, the following terms used in the specificationand claims have the following meanings set out below.

It is to be appreciated that references to “treating” or “treatment”include prophylaxis as well as the alleviation of established symptomsof a condition. “Treating” or “treatment” of a state, disorder orcondition therefore includes: (1) preventing or delaying the appearanceof clinical symptoms of the state, disorder or condition developing in ahuman that may be afflicted with or predisposed to the state, disorderor condition but does not yet experience or display clinical orsubclinical symptoms of the state, disorder or condition, (2) inhibitingthe state, disorder or condition, i.e., arresting, reducing or delayingthe development of the disease or a relapse thereof (in case ofmaintenance treatment) or at least one clinical or subclinical symptomthereof, or (3) relieving or attenuating the disease, i.e., causingregression of the state, disorder or condition or at least one of itsclinical or subclinical symptoms.

A “therapeutically effective amount” means the amount of a compoundthat, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups. References to individual alkyl groups suchas “propyl” are specific for the straight chain version only andreferences to individual branched chain alkyl groups such as “isopropyl”are specific for the branched chain version only. For example,“(1-6C)alkyl” includes (1-4C)alkyl, (1-3C)alkyl, propyl, isopropyl andt-butyl. A similar convention applies to other radicals, for example“phenyl(1-6C)alkyl” includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyland 2-phenylethyl.

The term “(m-nC)” or “(m-nC) group” used alone or as a prefix, refers toany group having m to n carbon atoms.

“(3-8C)cycloalkyl” means a hydrocarbon ring containing from 3 to 8carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl or bicycle[2.2.2]octane, bicycle[2.1.1]hexane,bicycle[1.1.1]pentane and bicyclo[2.2.1]heptyl.

The term “(1-8C)heteroalkyl” refers to an alkyl chain comprising 1-8carbon atoms which additionally comprises one, two or three heteroatomspresent within the alkyl chain which are selected from the groupconsisting of N, O, or S.

The term “halo” refers to fluoro, chloro, bromo and iodo.

The term “fluoroalkyl” is used herein to refer to an alkyl group inwhich one or more hydrogen atoms have been replaced by fluorine atoms.Examples of fluoroalkyl groups include —CHF₂, —CH₂CF₃, or perfluoroalkylgroups such as —CF₃ or —CF₂CF₃.

The term “fluoroalkoxy” is used herein to refer to an alkoxy group inwhich one or more hydrogen atoms have been replaced by fluorine atoms.Examples of fluoroalkoxy groups include —OCHF₂, —OCH₂CF₃, orperfluoroalkoxy groups such as —OCF₃ or —OCF₂CF₃.

The term “heterocyclyl”, “heterocyclic” or “heterocycle” means anon-aromatic saturated or partially saturated monocyclic, fused,bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclicheterocyclic rings contain from about 3 to 12 (suitably from 3 to 7)ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selectedfrom nitrogen, oxygen or sulfur in the ring. Bicyclic heterocyclescontain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in thering. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridgedring systems. Examples of heterocyclic groups include cyclic ethers suchas oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substitutedcyclic ethers. Heterocycles containing nitrogen include, for example,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl,tetrahydropyrazolyl, and the like. Typical sulfur containingheterocycles include tetrahydrothienyl, dihydro-1,3-dithiol,tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocyclesinclude dihydro-oxathiolyl, tetrahydro-oxazolyl, tetrahydro-oxadiazolyl,tetrahydrodioxazolyl, tetrahydro-oxathiazolyl, hexahydrotriazinyl,tetrahydro-oxazinyl, morpholinyl, thiomorpholinyl,tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl,octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocyclescontaining sulfur, the oxidized sulfur heterocycles containing SO or SO₂groups are also included. Examples include the sulfoxide and sulfoneforms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene1,1-dioxide and thiomorpholinyl 1,1-dioxide. A suitable value for aheterocyclyl group which bears 1 or 2 oxo (═O) or thioxo (═S)substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl,2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl,2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.Particular heterocyclyl groups are saturated monocyclic 3 to 7 memberedheterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen,oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl,tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl,tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl orhomopiperazinyl. As the skilled person would appreciate, any heterocyclemay be linked to another group via any suitable atom, such as via acarbon or nitrogen atom. However, reference herein to piperidino ormorpholino refers to a piperidin-1-yl or morpholin-4-yl ring that islinked via the ring nitrogen.

By “bridged ring systems” is meant ring systems in which two rings sharemore than two atoms, see for example Advanced Organic Chemistry, byJerry March, 4^(th) Edition, Wiley Interscience, pages 131-133, 1992.Examples of bridged heterocyclyl ring systems include,aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane,aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane and quinuclidine.

By “spiro bi-cyclic ring systems” we mean that the two ring systemsshare one common spiro carbon atom, i.e. the heterocyclic ring is linkedto a further carbocyclic or heterocyclic ring through a single commonspiro carbon atom. Examples of spiro ring systems include6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane,2-azaspiro[3.3]heptanes, 2-oxa-6-azaspiro[3.3]heptanes,7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane,2-oxa-7-azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.

“Heterocyclyl(m-nC)alkyl” means a heterocyclyl group covalently attachedto a (m-nC)alkylene group, both of which are defined herein.

The term “heteroaryl” or “heteroaromatic” means an aromatic mono-, bi-,or polycyclic ring incorporating one or more (for example 1-4,particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen orsulfur. Examples of heteroaryl groups are monocyclic and bicyclic groupscontaining from five to twelve ring members, and more usually from fiveto ten ring members. The heteroaryl group can be, for example, a 5- or6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, forexample a bicyclic structure formed from fused five and six memberedrings or two fused six membered rings. Each ring may contain up to aboutfour heteroatoms typically selected from nitrogen, sulfur and oxygen.Typically the heteroaryl ring will contain up to 3 heteroatoms, moreusually up to 2, for example a single heteroatom. In one embodiment, theheteroaryl ring contains at least one ring nitrogen atom. The nitrogenatoms in the heteroaryl rings can be basic, as in the case of animidazole or pyridine, or essentially non-basic as in the case of anindole or pyrrole nitrogen. In general the number of basic nitrogenatoms present in the heteroaryl group, including any amino groupsubstituents of the ring, will be less than five.

Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl,isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl,thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl,benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl,benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl,isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl,naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl,pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl,5H-pyrido[2,3-d]-o-oxazinyl, 1H-pyrazolo[4,3-d]-oxazolyl,4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl,imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl. “Heteroaryl”also covers partially aromatic bi- or polycyclic ring systems wherein atleast one ring is an aromatic ring and one or more of the other ring(s)is a non-aromatic, saturated or partially saturated ring, provided atleast one ring contains one or more heteroatoms selected from nitrogen,oxygen or sulfur. Examples of partially aromatic heteroaryl groupsinclude for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl,2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl,dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl,2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl,indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl,1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

Examples of five membered heteroaryl groups include but are not limitedto pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl,oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazolyl, triazolyl and tetrazolyl groups.

Examples of six membered heteroaryl groups include but are not limitedto pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

A bicyclic heteroaryl group may be, for example, a group selected from:

-   a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2    or 3 ring heteroatoms;-   b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2    or 3 ring heteroatoms;-   c) a pyrimidine ring fused to a 5- or 6-membered ring containing 1    or 2 ring heteroatoms;-   d) a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2    or 3 ring heteroatoms;-   e) a pyrazole ring fused to a 5- or 6-membered ring containing 1 or    2 ring heteroatoms;-   f) a pyrazine ring fused to a 5- or 6-membered ring containing 1 or    2 ring heteroatoms;-   g) an imidazole ring fused to a 5- or 6-membered ring containing 1    or 2 ring heteroatoms;-   h) an oxazole ring fused to a 5- or 6-membered ring containing 1 or    2 ring heteroatoms;-   i) an isoxazole ring fused to a 5- or 6-membered ring containing 1    or 2 ring heteroatoms;-   j) a thiazole ring fused to a 5- or 6-membered ring containing 1 or    2 ring heteroatoms;-   k) an isothiazole ring fused to a 5- or 6-membered ring containing 1    or 2 ring heteroatoms;-   l) a thiophene ring fused to a 5- or 6-membered ring containing 1, 2    or 3 ring heteroatoms;-   m) a furan ring fused to a 5- or 6-membered ring containing 1, 2 or    3 ring heteroatoms;-   n) a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring    containing 1, 2 or 3 ring heteroatoms; and-   o) a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic    ring containing 1, 2 or 3 ring heteroatoms.

Particular examples of bicyclic heteroaryl groups containing a sixmembered ring fused to a five membered ring include but are not limitedto benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl,indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl(e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine,and pyrazolopyridinyl groups.

Particular examples of bicyclic heteroaryl groups containing two fusedsix membered rings include but are not limited to quinolinyl,isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl,chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl,benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalazinyl, naphthyridinyl and pteridinyl groups.

“Heteroaryl(m-nC)alkyl” means a heteroaryl group covalently attached toa (m-nC)alkylene group, both of which are defined herein. Examples ofheteroaralkyl groups include pyridin-3-ylmethyl,3-(benzofuran-2-yl)propyl, and the like.

The term “aryl” means a cyclic or polycyclic aromatic ring having from 5to 12 carbon atoms. The term aryl includes both monovalent species anddivalent species. Examples of aryl groups include, but are not limitedto, phenyl, biphenyl, naphthyl and the like. In particular embodiment,an aryl is phenyl.

The term “aryl(m-nC)alkyl” means an aryl group covalently attached to a(m-nC)alkylene group, both of which are defined herein. Examples ofaryl-(m-nC)alkyl groups include benzyl, phenylethyl, and the like.

This specification also makes use of several composite terms to describegroups comprising more than one functionality. Such terms will beunderstood by a person skilled in the art. For exampleheterocyclyl(m-nC)alkyl comprises (m-nC)alkyl substituted byheterocyclyl.

The term “optionally substituted” refers to either groups, structures,or molecules that are substituted and those that are not substituted.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

The phrase “compound of the invention” means those compounds which aredisclosed herein, both generically and specifically.

Compounds of the Invention

In one aspect, the present invention provides a compound of formula Ishown below:

wherein:

-   W is N or C—R₃;-   X is CH or N;-   Z is N or C—H;-   R₁ is selected from chloro, (1-6C)alkyl, (1-8C)heteroalkyl, aryl,    aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl,    heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl,    (3-8C)cycloalkyl(1-2C)alkyl, NR₇R₈, OR₉, C(O)R₉, C(O)OR₉, OC(O)R₉,    N(R₁₀)OR₉, N(R₁₀)C(O)OR₉, C(O)N(R₁₀)R₉, N(R₁₀)C(O)R₉, S(O)_(p)R₉    (where p is 0, 1 or 2), SO₂N(R₁₀)R₉, N(R₁₀)SO₂R₉, N(R₁₀)SOR₉ or    SON(R₁₀)R₉;-   and wherein R₁ is optionally substituted by one or more substituent    groups selected from fluoro, chloro, trifluoromethyl,    trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl,    sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(O)_(q)CH₃ (where q is 0, 1    or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl,    heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl,    heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, or    (3-8C)cycloalkyl(1-2C)alkyl,-   and wherein any (1-4C)alkyl, (1-4C)alkoxy, aryl, heteroaryl,    heterocyclyl, or (3-8C)cycloalkyl moiety present within a    substituent group on R₁ is optionally further substituted by fluoro,    chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy,    amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NR_(a)R_(b),    OR_(a), C(O)R_(a), C(O)OR_(a), OC(O)R_(a), N(R_(b))OR_(a),    C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is 0, 1    or 2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a), wherein R_(a) and    R_(b) are each independently selected from H or (1-4C)alkyl;-   R₃ is hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, halo, CF₃, CN and    (1-4C)alkoxy;-   R₄ is hydrogen, (1-3C)alkyl, (1-3C)alkoxy, fluoro, chloro or CF₃;-   Ar has the formula:

wherein:

-   (i) all of A₁, A₂ and A₃ are CH;-   (ii) one of A₁, A₂ and A₃ is N and the others are CH; or-   (iii) two of A₁, A₂ and A₃ are N and the other is CH;-   R₅ is selected from hydrogen, cyano, (1-3C)alkyl, (1-3C)fluoroalkyl,    (1-3C)alkoxy, (1-3C)fluoroalkoxy, halo, (1-3C)alkanoyl, C(O)NR₁₅R₁₆    or S(O)₂NR₁₅R₁₆, and wherein R₁₅ and R₁₆ are each independently    selected from H or (1-3C)alkyl,-   and wherein any alkyl or alkoxy moities present within a R₅    substituent group are optionally further substituted by hydroxy or    methoxy;-   R₆ is selected from halo, trifluoromethyl, trifluoromethoxy, cyano,    nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, ureido,    (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,-   or R₆ is a group of the formula:    -L¹-L²-R₁₇

wherein

-   L¹ is absent or a linker group of the formula —[CR₁₈R₁₉]_(n)— in    which n is an integer selected from 1, 2, 3 or 4, and R₁₈ and R₁₉    are each independently selected from hydrogen or (1-2C)alkyl;-   L² is absent or is selected from O, S, SO, SO₂, N(R₂₀), C(O), C(O)O,    OC(O), CH(OR₂₀), C(O)N(R₂₀), N(R₂₀)C(O), N(R₂₀)C(O)N(R₂₁),    S(O)₂N(R₂₀), or N(R₂₁)SO₂, wherein R₂₀ and R₂₁ are each    independently selected from hydrogen or (1-2C)alkyl; and-   R₁₇ is (1-6C)alkyl, aryl, aryl-(1-6C)alkyl, (3-6C)cycloalkyl,    (3-6C)cycloalkyl-(1-4C)alkyl, heteroaryl, heteroaryl-(1-4C)alkyl,    heterocyclyl, heterocyclyl-(1-4C)alkyl,-   and wherein R₁₇ is optionally further substituted by one or more    substituent groups independently selected from oxo, halo, cyano,    nitro, hydroxy, NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl,    (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-5C)alkanoyl,    (1-5C)alkylsulphonyl, heterocyclyl, heterocyclyl-(1-2C)alkyl,    heteroaryl, heteroaryl-(1-2C)alkyl, CONR₂₂R₂₃, and SO₂NR₂₂R₂₃;    wherein R₂₂ and R₂₃ are each independently selected from hydrogen,    (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;-   and wherein when said substituent group comprises an alkyl,    cycloalkyl, heterocyclyl or heteroaryl moiety then said moiety is    optionally further substituted by hydroxy, fluoro, chloro, cyano,    CF₃, OCF₃, (1-2C)alkyl, (1-2C)alkoxy, SO₂(1-2C)alkyl or NR_(e)R_(f)    (where R_(e) and R_(f) are each independently selected from    hydrogen, (1-3C)alkyl, (3-6C)cycloalkyl, or    (3-6C)cycloalkyl(1-2C)alkyl);-   or R₁₇ is a group having the formula:    -L³-L⁴-R₂₄-   L³ is absent or a linker group of the formula —[CR₂₅R₂₆]_(n)— in    which n is an integer selected from 1, 2, 3 or 4, and R₂₅ and R₂₆    are each independently selected from hydrogen or (1-2C)alkyl;-   L⁴ is absent or is selected from O, S, SO, SO₂, N(R₂₇), C(O), C(O)O,    OC(O), CH(OR₂₇), C(O)N(R₂₇), N(R₂₇)C(O), N(R₂₇)C(O)N(R₂₈),    S(O)₂N(R₂₇), or N(R₂₈)SO₂, wherein R₂₇ and R₂₈ are each    independently selected from hydrogen or (1-2C)alkyl; and-   R₂₄ is (1-6C)alkyl, aryl, aryl-(1-6C)alkyl, (3-6C)cycloalkyl,    (3-6C)cycloalkyl-(1-4C)alkyl, heteroaryl, heteroaryl-(1-4C)alkyl,    heterocyclyl, heterocyclyl-(1-4C)alkyl;-   R₈ and R₉ are each independently selected from hydrogen,    (1-6C)alkyl, (1-6C)alkoxy, (3-9C)cycloalkyl,    (3-9C)cycloalkyl-(1-2C)alkyl, aryl, aryl-(1-2C)alkyl, heterocyclyl,    heterocyclyl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, and    wherein R₈ and R₉ are optionally further substituted by one or more    substituents selected from hydroxy, fluoro, chloro, cyano, CF₃, OCF₃    (1-2C)alkyl or (1-2C)alkoxy;-   R₇ and R₁₀ are independently selected from hydrogen, (1-6C)alkyl,    (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-2C)alkyl, and wherein R₇ and    R₁₀ are optionally further substituted by one or more substituents    selected from hydroxy, fluoro, chloro, cyano, CF₃, OCF₃, (1-2C)alkyl    or (1-2C)alkoxy;-   subject to the proviso that:-   X is only N when Z is N;-   W is only N when X and Z are both N; and-   R₆ is not methoxy when R₁ is S(O)₂R₉ and R₉ is heterocyclyl;-   or a pharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a compound of formulaI

wherein:

-   W, X, Z, R₃, R₄, R₇, R₈, R₉ and R₁₀ are each as defined above;-   R₁ is selected from chloro, (1-6C)alkyl, (1-8C)heteroalkyl, aryl,    aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl,    heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl,    (3-8C)cycloalkyl(1-2C)alkyl, NR₇R₈, OR₉, C(O)R₉, C(O)OR₉, OC(O)R₉,    N(R₁₀)OR₉, N(R₁₀)C(O)OR₉, C(O)N(R₁₀)R₉, N(R₁₀)C(O)R₉, S(O)_(p)R₉    (where p is 0, 1 or 2), SO₂N(R₁₀)R₉ or N(R₁₀)SO₂R₉;-   and wherein R₁ is optionally substituted by one or more substituent    groups selected from fluoro, chloro, trifluoromethyl,    trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl,    sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(O)_(q)CH₃ (where q is 0, 1    or 2), methylamino or dimethylamino, aryl, aryl(1-2C)alkyl,    heteroaryl, heteroaryl(1-2C)alkyl, heterocyclyl,    heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, or    (3-8C)cycloalkyl(1-2C)alkyl,-   and wherein any (1-4C)alkyl, (1-4C)alkoxy, aryl, heteroaryl,    heterocyclyl, or (3-8C)cycloalkyl moiety present within a    substituent group on R₁ is optionally further substituted by fluoro,    chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy,    amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NR_(a)R_(b),    OR_(a), C(O)R_(a), C(O)OR_(a), OC(O)R_(a), N(R_(b))OR_(a),    C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is 0, 1    or 2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a), wherein R_(a) and    R_(b) are each independently selected from H or (1-4C)alkyl;-   Ar has the formula:

wherein:

-   A₁, A₂, A₃, R₆ are as defined above;-   (i) of A₁, A₂ and A₃ is N and the others are CH; or-   (ii) two of A₁, A₂ and A₃ are N and the other is CH;-   R₅ is selected from hydrogen, cyano, (1-3C)alkyl,    (1-3C)perfluoroalkyl, (1-3C)alkoxy, (1-3C)fluoroalkoxy, halo,    (1-3C)alkanoyl, C(O)NR₁₅R₁₆ or S(O)₂NR₁₅R₁₆, and wherein R₁₅ and R₁₆    are each independently selected from H or (1-3C)alkyl,-   and wherein any alkyl or alkoxy moities present within a R₅    substituent group are optionally further substituted by hydroxy or    methoxy;-   R₆ is selected from halo, trifluoromethyl, trifluoromethoxy, cyano,    nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl, ureido,    (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl,-   or R₆ is a group of the formula:    -L¹-L²-R₁₇    wherein-   L¹ is absent or a linker group of the formula —[CR₁₈R₁₉]_(n)— in    which n is an integer selected from 1, 2, 3 or 4, and R₁₈ and R₁₉    are each independently selected from hydrogen or (1-2C)alkyl;-   L² is absent or is selected from O, S, SO, SO₂, N(R₂₀), C(O), C(O)O,    OC(O), CH(OR₂₀), C(O)N(R₂₀), N(R₂₀)C(O), N(R₂₀)C(O)N(R₂₁),    S(O)₂N(R₂₀), or N(R₂₁)SO₂, wherein R₂₀ and R₂₁ are each    independently selected from hydrogen or (1-2C)alkyl; and-   R₁₇ is (1-6C)alkyl, aryl, aryl-(1-6C)alkyl, (3-6C)cycloalkyl,    (3-6C)cycloalkyl-(1-4C)alkyl, heteroaryl, heteroaryl-(1-4C)alkyl,    heterocyclyl, heterocyclyl-(1-4C)alkyl,-   and wherein R₁₇ is optionally further substituted by one or more    substituent groups independently selected from oxo, halo, cyano,    nitro, hydroxy, NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl,    (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-5C)alkanoyl,    (1-5C)alkylsulphonyl, heterocyclyl, heterocyclyl-(1-2C)alkyl,    heteroaryl, heteroaryl-(1-2C)alkyl, CONR₂₂R₂₃, and SO₂NR₂₂R₂₃    wherein R₂₂ and R₂₃ are each independently selected from hydrogen,    (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;-   and wherein when said substituent group comprises an alkyl,    cycloalkyl, heterocyclyl or heteroaryl moiety then said moiety is    optionally further substituted by hydroxy, fluoro, chloro, cyano,    CF₃, OCF₃, (1-2C)alkyl, (1-2C)alkoxy, SO₂(1-2C)alkyl or NR_(e)R_(f)    (where R_(e) and R_(f) are each independently selected from    hydrogen, (1-3C)alkyl, (3-6C)cycloalkyl, or    (3-6C)cycloalkyl(1-2C)alkyl);-   subject to the proviso that:-   X is only N when Z is N;-   W is only N when X and Z are both N; and-   R₆ is not methoxy when R₁ is S(O)₂R₉ and R₉ is heterocyclyl;-   or a pharmaceutically acceptable salt or solvate thereof.

Suitably, R₆ is not methoxy when R₁ is S(O)₂R₉.

Suitably, R₆ is not methoxy when R₁ is S(O)_(p)R₉ (where p is 0, 1 or2).

In an embodiment, R₁ is not S(O)_(p)R₉ (where p is 0, 1 or 2).

Particular compounds of the invention include, for example, compounds ofthe formula I, or pharmaceutically acceptable salts or solvates thereof,wherein, unless otherwise stated, each of X, W, Z, R₁, R₃, R₄, Ar, R₅,R₆, R₇, R₈, R₉, R₁₀, R₁₅, R₁₆, R₁₇, R₁₈, R₁₉, R₂₀, R₂₁, R₂₂, R₂₃, R₂₄,R₂₅, R₂₆, R₂₇, R₂₈, R_(a), R_(b), R_(e) and R_(f), has any of themeanings defined hereinbefore or in any one of paragraphs (1) to (63)hereinafter:—

-   (1) X is CH;-   (2) X and Z are both N;-   (3) Z is N;-   (4) Z is C—H;-   (5) R₁ is selected from (1-6C)alkyl, (1-8C)heteroalkyl, phenyl,    phenyl(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6 membered    heteroaryl(1-2C)alkyl, 3 to 9 membered heterocyclyl, 3 to 9 membered    heterocyclyl(1-2C)alkyl, (3-6C)cycloalkyl,    (3-6C)cycloalkyl(1-2C)alkyl, NR₇R₈, OR₉, C(O)R₉, C(O)OR₉, OC(O)R₉,    N(R₁₀)OR₉, N(R₁₀)C(O)OR₉, C(O)N(R₁₀)R₉, N(R₁₀)C(O)R₉, S(O)_(p)R₉    (where p is 0, 1 or 2), SO₂N(R₁₀)R₉, N(R₁₀)SO₂R₉, N(R₁₀)SOR₉ or    SON(R₁₀)R₉;-   and wherein R₁ is optionally substituted by one or more substituent    groups selected from fluoro, chloro, trifluoromethyl,    trifluoromethoxy, cyano, hydroxy, amino, carboxy, carbamoyl,    sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(O)_(q)CH₃ (where q is 0, 1    or 2), methylamino or dimethylamino, phenyl, phenyl(1-2C)alkyl, 5 or    6 membered heteroaryl, 5 or 6 membered heteroaryl(1-2C)alkyl, 3 to 6    membered heterocyclyl, 3 to 6 membered heterocyclyl(1-2C)alkyl,    (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl, and wherein any    (1-4C)alkyl, (1-4C)alkoxy, phenyl, heteroaryl, heterocyclyl, or    (3-6C)cycloalkyl moiety present within a substituent group on R₁ is    optionally further substituted by fluoro, chloro, trifluoromethyl,    trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl,    sulphamoyl, (1-4C)alkyl, NR_(a)R_(b), OR_(a), C(O)R_(a), C(O)OR_(a),    OC(O)R_(a), N(R_(b))OR_(a), C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a),    S(O)_(p)R_(a) (where p is 0, 1 or 2), SO₂N(R_(b))R_(a), or    N(R_(b))SO₂R_(a), wherein R_(a) and R_(b) are each independently    selected from H or (1-4C)alkyl;-   (6) R₁ is selected from (1-6C)alkyl, phenyl, phenyl(1-2C)alkyl, 5 or    6 membered heteroaryl, 5 or 6 membered heteroaryl(1-2C)alkyl, 3 to 9    membered heterocyclyl, 3 to 9 membered heterocyclyl(1-2C)alkyl,    (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, NR₇R₈, OR₉, C(O)R₉,    C(O)OR₉, OC(O)R₉, N(R₁₀)OR₉, N(R₁₀)C(O)OR₉, C(O)N(R₁₀)R₉,    N(R₁₀)C(O)R₉, S(O)_(p)R₉ (where p is 0, 1 or 2), SO₂N(R₁₀)R₉,    N(R₁₀)SOR₉ or N(R₁₀)SO₂R₉;-   and wherein R₁ is optionally substituted by one or more substituent    groups selected from fluoro, chloro, trifluoromethyl,    trifluoromethoxy, cyano, hydroxy, amino, carbamoyl, sulphamoyl,    (1-4C)alkyl, (1-4C)alkoxy, S(O)_(q)CH₃ (where q is 0, 1 or 2),    methylamino or dimethylamino, 5 or 6 membered heteroaryl, 5 or 6    membered heteroaryl(1-2C)alkyl, 3 to 6 membered heterocyclyl, 3 to 6    membered heterocyclyl(1-2C)alkyl, (3-6C)cycloalkyl, or    (3-6C)cycloalkyl(1-2C)alkyl,-   and wherein any (1-4C)alkyl, (1-4C)alkoxy, heteroaryl, heterocyclyl,    or (3-6C)cycloalkyl moiety present within a substituent group on R₁    is optionally further substituted by fluoro, chloro,    trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, carboxy,    carbamoyl, sulphamoyl, (1-4C)alkyl, NR_(a)R_(b), OR_(a), C(O)R_(a),    C(O)OR_(a), OC(O)R_(a), N(R_(b))OR_(a), C(O)N(R_(b))R_(a),    N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is 0, 1 or 2),    SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a), wherein R_(a) and R_(b) are    each independently selected from H or (1-4C)alkyl;-   (7) R₁ is selected from (1-6C)alkyl, phenyl, phenyl(1-2C)alkyl, 5 or    6 membered heteroaryl, 5 or 6 membered heteroaryl(1-2C)alkyl, 3 to 9    membered heterocyclyl, 3 to 9 membered heterocyclyl(1-2C)alkyl,    (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, NR₇R₈, OR₉, C(O)R₉,    C(O)OR₉, OC(O)R₉, N(R₁₀)OR₉, N(R₁₀)C(O)OR₉, C(O)N(R₁₀)R₉,    N(R₁₀)C(O)R₉, S(O)_(p)R₉ (where p is 0, 1 or 2), SO₂N(R₁₀)R₉,    N(R₁₀)SOR₉ or N(R₁₀)SO₂R₉;-   and wherein R₁ is optionally substituted by one or more substituent    groups selected from fluoro, chloro, trifluoromethyl,    trifluoromethoxy, cyano, hydroxy, amino, carbamoyl, sulphamoyl,    (1-4C)alkyl, (1-4C)alkoxy, S(O)_(p)CH₃ (where q is 0, 1 or 2),    methylamino or dimethylamino, 5 or 6 membered heteroaryl, or 3 to 6    membered heterocyclyl, and wherein any (1-4C)alkyl, (1-4C)alkoxy,    heteroaryl, or heterocyclyl moiety present within a substituent    group on R₁ is optionally further substituted by fluoro, chloro,    trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, carboxy,    carbamoyl, sulphamoyl, (1-4C)alkyl, NR_(a)R_(b), OR_(a), C(O)R_(a),    C(O)OR_(a), OC(O)R_(a), N(R_(b))OR_(a), C(O)N(R_(b))R_(a),    N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is 0, 1 or 2),    SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a), wherein R_(a) and R_(b) are    each independently selected from H or (1-4C)alkyl;-   (8) R₁ is selected from (1-6C)alkyl, phenyl, phenyl(1-2C)alkyl, 5 or    6 membered heteroaryl, 5 or 6 membered heteroaryl(1-2C)alkyl, 3 to 9    membered heterocyclyl, 3 to 9 membered heterocyclyl(1-2C)alkyl,    (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl, NR₇R₈, OR₉, C(O)R₉,    C(O)OR₉, OC(O)R₉, N(R₁₀)OR₉, N(R₁₀)C(O)OR₉, C(O)N(R₁₀)R₉,    N(R₁₀)C(O)R₉, S(O)_(p)R₉ (where p is 0, 1 or 2), SO₂N(R₁₀)R₉,    N(R₁₀)SOR₉ or N(R₁₀)SO₂R₉;-   and wherein R₁ is optionally substituted by one or more substituent    groups selected from fluoro, chloro, trifluoromethyl,    trifluoromethoxy, cyano, hydroxy, amino, carbamoyl, sulphamoyl,    (1-4C)alkyl, (1-4C)alkoxy, S(O)_(p)CH₃ (where q is 0, 1 or 2),    methylamino or dimethylamino, 5 or 6 membered heteroaryl, or 4 to 6    membered heterocyclyl, and wherein any (1-4C)alkyl, (1-4C)alkoxy,    heteroaryl, or heterocyclyl moiety present within a substituent    group on R₁ is optionally further substituted by fluoro, chloro,    trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, carbamoyl,    sulphamoyl, (1-4C)alkyl, NR_(a)R_(b), OR_(a), C(O)R_(a), C(O)OR_(a),    OC(O)R_(a), C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a)    (where p is 0, 1 or 2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a),    wherein R_(a) and R_(b) are each independently selected from H or    (1-4C)alkyl;-   (9) R₁ is selected from phenyl, 5 or 6 membered heteroaryl, 3 to 9    membered heterocyclyl, 3 to 9 membered heterocyclyl(1-2C)alkyl,    (3-6C)cycloalkyl, NR₇R₈, OR₉, C(O)R₉, C(O)OR₉, OC(O)R₉, N(R₁₀)OR₉,    C(O)N(R₁₀)R₉, N(R₁₀)C(O)R₉, S(O)_(p)R₉ (where p is 0, 1 or 2),    SO₂N(R₁₀)R₉, N(R₁₀)SOR₉ or N(R₁₀)SO₂R₉;-   and wherein R₁ is optionally substituted by one or more substituent    groups selected from fluoro, chloro, trifluoromethyl,    trifluoromethoxy, cyano, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy,    S(O)_(q)CH₃ (where q is 0, 1 or 2), methylamino or dimethylamino, or    4 to 6 membered heterocyclyl,-   and wherein any (1-4C)alkyl or heterocyclyl moiety present within a    substituent group on R₁ is optionally further substituted by fluoro,    chloro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino,    carbamoyl, sulphamoyl, (1-4C)alkyl, NR_(a)R_(b), OR_(a), C(O)R_(a),    C(O)OR_(a), OC(O)R_(a), C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a),    S(O)_(p)R_(a) (where p is 0, 1 or 2), SO₂N(R_(b))R_(a), or    N(R_(b))SO₂R_(a), wherein R_(a) and R_(b) are each independently    selected from H or (1-4C)alkyl;-   (10) R₁ is selected from phenyl, 5 or 6 membered heteroaryl, 3 to 9    membered heterocyclyl, 3 to 9 membered heterocyclyl(1-2C)alkyl,    (3-6C)cycloalkyl, NR₇R₈, OR₉, N(R₁₀)OR₉, C(O)N(R₁₀)R₉, N(R₁₀)C(O)R₉,    S(O)_(p)R₉ (where p is 0, 1 or 2), SO₂N(R₁₀)R₉, N(R₁₀)SOR₉ or    N(R₁₀)SO₂R₉;-   and wherein R₁ is optionally substituted by one or more substituent    groups selected from fluoro, chloro, trifluoromethyl,    trifluoromethoxy, cyano, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy,    S(O)_(q)CH₃ (where q is 0, 1 or 2), methylamino or dimethylamino, or    4 to 6 membered heterocyclyl,-   and wherein any (1-4C)alkyl, heteroaryl, or heterocyclyl moiety    present within a substituent group on R₁ is optionally further    substituted by fluoro, chloro, trifluoromethyl, trifluoromethoxy,    cyano, hydroxy, amino, carbamoyl, sulphamoyl, (1-4C)alkyl,    NR_(a)R_(b), OR_(a), C(O)R_(a), C(O)OR_(a), OC(O)R_(a),    C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is 0, 1    or 2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a), wherein R_(a) and    R_(b) are each independently selected from H or (1-4C)alkyl;-   (11) R₁ is selected from phenyl, 5 or 6 membered heteroaryl, 3 to 9    membered heterocyclyl, 3 to 9 membered heterocyclyl(1-2C)alkyl,    (3-6C)cycloalkyl, NR₇R₈, OR₉, N(R₁₀)OR₉, N(R₁₀)SO₂R₉, N(R₁₀)SOR₉ or    S(O)_(p)R₉ (where p is 0, 1 or 2);-   and wherein R₁ is optionally substituted by one or more substituent    groups selected from fluoro, chloro, trifluoromethyl,    trifluoromethoxy, cyano, hydroxy, amino, (1-4C)alkyl, (1-4C)alkoxy,    S(O)_(q)CH₃ (where q is 0, 1 or 2), methylamino or dimethylamino, or    4 to 6 membered heterocyclyl,-   and wherein any (1-4C)alkyl, heteroaryl, or heterocyclyl moiety    present within a substituent group on R₁ is optionally further    substituted by fluoro, chloro, trifluoromethyl, trifluoromethoxy,    cyano, hydroxy, amino, carbamoyl, sulphamoyl, (1-4C)alkyl,    NR_(a)R_(b), OR_(a), C(O)R_(a), C(O)OR_(a), OC(O)R_(a),    C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is 0, 1    or 2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a), wherein R_(a) and    R_(b) are each independently selected from H or (1-4C)alkyl;-   (12) R₁ is selected from phenyl, 5 or 6 membered heteroaryl, 3 to 9    membered heterocyclyl, 3 to 9 membered heterocyclyl(1-2C)alkyl,    (3-6C)cycloalkyl, NR₇R₈, OR₉, N(R₁₀)OR₉, N(R₁₀)SO₂R₉, N(R₁₀)SOR₉ or    S(O)_(p)R₉ (where p is 0);-   and wherein R₁ is optionally substituted by one or more substituent    groups selected from fluoro, chloro, trifluoromethyl,    trifluoromethoxy, cyano, hydroxy, amino, carboxy, carbamoyl,    sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(O)_(p)CH₃ (where q is 0, 1    or 2), methylamino or dimethylamino, phenyl, phenyl(1-2C)alkyl, 5 or    6 membered heteroaryl, 5 or 6 membered heteroaryl(1-2C)alkyl, 3 to 6    membered heterocyclyl, 3 to 6 membered heterocyclyl(1-2C)alkyl,    (3-6C)cycloalkyl, or (3-6C)cycloalkyl(1-2C)alkyl,-   and wherein any (1-4C)alkyl, (1-4C)alkoxy, aryl, heteroaryl,    heterocyclyl, or (3-6C)cycloalkyl moiety present within a    substituent group on R₁ is optionally further substituted by fluoro,    chloro, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy,    amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NR_(a)R_(b),    OR_(a), C(O)R_(a), C(O)OR_(a), OC(O)R_(a), N(R_(b))OR_(a),    C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is 0, 1    or 2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a), wherein R_(a) and    R_(b) are each independently selected from H or (1-4C)alkyl;-   (13) R₁ is selected from phenyl, 5 or 6 membered heteroaryl, 3 to 9    membered heterocyclyl, 3 to 9 membered heterocyclyl(1-2C)alkyl,    (3-6C)cycloalkyl, NR₇R₈, N(R₁₀)OR₉, N(R₁₀)SO₂R₉, N(R₁₀)SOR₉ or OR₉;-   and wherein R₁ is optionally substituted by one or more substituent    groups selected from fluoro, chloro, trifluoromethyl,    trifluoromethoxy, cyano, hydroxy, amino, carboxy, carbamoyl,    sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(O)_(p)CH₃ (where q is 0, 1    or 2), methylamino or dimethylamino, phenyl, 5 or 6 membered    heteroaryl, 3 to 6 membered heterocyclyl, or (3-6C)cycloalkyl,-   and wherein any (1-4C)alkyl, (1-4C)alkoxy, phenyl, heteroaryl,    heterocyclyl, or (3-6C)cycloalkyl group present within a substituent    group on R₁ is optionally further substituted by fluoro, chloro,    trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino,    carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NR_(a)R_(b), OR_(a),    C(O)R_(a), C(O)OR_(a), OC(O)R_(a), N(R_(b))OR_(a),    C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is 0, 1    or 2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a), wherein R_(a) and    R_(b) are each independently selected from H or (1-4C)alkyl;-   (14) R₁ is selected from phenyl, 5 or 6 membered heteroaryl, 3 to 9    membered heterocyclyl, 3 to 9 membered heterocyclyl(1-2C)alkyl,    (4-6C)cycloalkyl, N(R₁₀)OR₉, N(R₁₀)SO₂R₉, N(R₁₀)SOR₉ or NR₇R₈;-   and wherein R₁ is optionally substituted by one or more substituent    groups selected from fluoro, chloro, trifluoromethyl,    trifluoromethoxy, cyano, hydroxy, amino, carboxy, carbamoyl,    sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(O)_(q)CH₃ (where q is 0, 1    or 2), methylamino or dimethylamino, phenyl, 5 or 6 membered    heteroaryl, 3 to 6 membered heterocyclyl, or (3-6C)cycloalkyl,-   and wherein any (1-4C)alkyl, (1-4C)alkoxy, phenyl, heteroaryl,    heterocyclyl, or (3-6C)cycloalkyl group present within a substituent    group on R₁ is optionally further substituted by fluoro, chloro,    trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino,    carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NR_(a)R_(b), OR_(a),    C(O)R_(a), C(O)OR_(a), OC(O)R_(a), N(R_(b))OR_(a),    C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is 0, 1    or 2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a), wherein R_(a) and    R_(b) are each independently selected from H or (1-4C)alkyl;-   (15) R₁ is selected from phenyl, 5 or 6 membered heteroaryl, 3 to 9    membered heterocyclyl, 3 to 9 membered heterocyclyl(1-2C)alkyl,    N(R₁₀)OR₉, N(R₁₀)SO₂R₉, N(R₁₀)SOR₉ or NR₇R₈;-   and wherein R₁ is optionally substituted by one or more substituent    groups selected from fluoro, chloro, trifluoromethyl,    trifluoromethoxy, cyano, hydroxy, amino, carboxy, carbamoyl,    sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(O)_(q)CH₃ (where q is 0, 1    or 2), methylamino or dimethylamino, phenyl, 5 or 6 membered    heteroaryl, 3 to 6 membered heterocyclyl, or (3-6C)cycloalkyl,-   and wherein any (1-4C)alkyl, (1-4C)alkoxy, phenyl, heteroaryl,    heterocyclyl, or (3-6C)cycloalkyl group present within a substituent    group on R₁ is optionally further substituted by fluoro, chloro,    trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino,    carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NR_(a)R_(b), OR_(a),    C(O)R_(a), C(O)OR_(a), OC(O)R_(a), N(R_(b))OR_(a),    C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is 0, 1    or 2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a), wherein R_(a) and    R_(b) are each independently selected from H or (1-4C)alkyl;-   (16) R₁ is a 3 to 9 membered nitrogen-linked heterocyclyl or NR₇R₈;-   and wherein 3 to 9 membered nitrogen-linked heterocyclyl is    optionally substituted by one or more substituent groups selected    from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano,    hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl,    (1-4C)alkoxy, S(O)_(q)CH₃ (where q is 0, 1 or 2), methylamino,    dimethylamino, phenyl, 5 or 6 membered heteroaryl, 3 to 6 membered    heterocyclyl, or (3-6C)cycloalkyl;-   R₇ is hydrogen; and-   R₈ is (1-6C)alkyl or a 3 to 9 membered heterocyclyl, each of which    is optionally substituted by one or more substituents selected from    hydroxyl, fluoro, chloro, cyano, CF₃, OCF₃, (1-2C)alkyl or    (1-2C)alkoxy;-   (17) R₁ is a 3 to 9 membered nitrogen-linked monocyclic, bicyclic,    or spiro bicyclic heterocyclyl or NR₇R₈;-   and wherein 3 to 9 membered nitrogen-linked heterocyclyl is    optionally substituted by one or more substituent groups selected    from fluoro, chloro, trifluoromethyl, trifluoromethoxy, cyano,    hydroxy, amino, carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl,    (1-4C)alkoxy, S(O)_(q)CH₃ (where q is 0, 1 or 2), methylamino or    dimethylamino;-   R₇ is hydrogen; and-   R₈ is (1-6C)alkyl or a 3 to 9 membered heterocyclyl, each of which    is optionally substituted by one or more substituents selected from    hydroxyl, fluoro, chloro, cyano, CF₃, OCF₃, (1-2C)alkyl or    (1-2C)alkoxy;-   (18) R₃ is hydrogen, (1-2C)alkyl, or (3-6C)cycloalkyl;-   (19) R₃ is hydrogen or (1-2C)alkyl;-   (20) R₃ is hydrogen or methyl;-   (21) R₃ is hydrogen;-   (22) R₃ is methyl;-   (23) R₃ is (3-6C)cycloalkyl;-   (24) R₄ is hydrogen, (1-2C)alkyl, (1-2C)alkoxy, fluoro, chloro or    CF₃;-   (25) R₄ is chloro, methoxy and ethyl;-   (26) R₄ is hydrogen or methyl;-   (27) R₄ is hydrogen;-   (28) R₄ is methyl;-   (29) Ar has the formula:

wherein:

-   (i) all of A₁, A₂ and A₃ are CH; or-   (ii) one of A₁, A₂ and A₃ is N and the others are CH;-   and R₅ and R₆ each have any one of the definitions set out herein;-   (30) Ar has the formula:

wherein:

-   (i) all of A₁, A₂ and A₃ are CH; or-   (ii) A₃ is CH and A₁ or A₂ are selected from N or CH;-   and R₅ and R₆ each have any one of the definitions set out herein;-   (31) Ar has the formula:

wherein:

-   (i) all of A₁, A₂ and A₃ are CH; or-   (ii) A₃ is CH and one of A₁ or A₂ is N and the other is CH;-   and R₅ and R₆ each have any one of the definitions set out herein;-   (32) Ar has the formula:

wherein:

-   (i) all of A₁, A₂ and A₃ are CH; or-   (ii) A₂ and A₃ are both CH and A₁ is N;-   and R₅ and R₆ each have any one of the definitions set out herein;-   (33) Ar has the formula:

wherein:

-   all of A₁, A₂ and A₃ are CH; or-   and R₅ and R₆ each have any one of the definitions set out herein;-   (34) R₅ is hydrogen, cyano, (1-3C)alkyl, (1-3C)perfluoroalkyl,    (1-3C)alkoxy, (1-3C) fluoroalkoxy, and halo, and wherein any alkyl    or alkoxy moities present within a R₅ substituent group are    optionally further substituted by hydroxy or methoxy;-   (35) R₅ is hydrogen, (1-3C)alkyl, (1-3C)alkoxy, (1-3C) fluoroalkoxy    and halo, and wherein any alkyl or alkoxy moities present within a    R₅ substituent group are optionally further substituted by methoxy;-   (36) R₅ is (1-2C)alkyl, CF₃, (1-2C)alkoxy, —OCF₂H, —OCF₃ or Cl;-   (37) R₅ is (1-2C)alkoxy or Cl;-   (38) R₅ is OCH₃;-   (39) R₅ is Cl;-   (40) R₆ is halogeno, trifluoromethyl, trifluoromethoxy, cyano,    hydroxy, amino, carboxy, carbamoyl, sulphamoyl,-   or R₆ is a group of the formula:    -L¹-L²-R₁₇

wherein

-   L¹ is absent or a linker group of the formula —[CR₁₈R₁₉]_(n)— in    which n is an integer selected from 1 or 2, and R₁₈ and R₁₉ are each    independently selected from hydrogen or methyl;-   L² is absent or is selected from O, S, SO, SO₂, N(R₂₀), C(O), C(O)O,    OC(O), CH(OR₂₀), C(O)N(R₂₀), N(R₂₀)C(O), N(R₂₀)C(O)N(R₂₁),    S(O)₂N(R₂₀), or N(R₂₀)SO₂, wherein R₂₀ and R₂₁ are each    independently selected from hydrogen or (1-2C)alkyl; and-   R₁₇ is (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6 membered    heteroaryl, or 3 to 8 membered heterocyclyl,-   and wherein R₁₇ is optionally further substituted by one or more    substituent groups independently selected from oxo, halo, cyano,    nitro, hydroxy, NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl,    (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-5C)alkanoyl,    (1-5C)alkylsulphonyl, 3 to 6 membered heterocyclyl, 3 to 6 membered    heterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6    membered heteroaryl-(1-2C)alkyl, CONR₂₂R₂₃, and SO₂NR₂₂R₂₃; wherein    R₂₂ and R₂₃ are each independently selected from hydrogen,    (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or    R₂₂ and R₂₃ can be linked such that, together with the nitrogen atom    to which they are attached, they form a 4-6 membered heterocyclic    ring;-   and wherein when said substituent group comprises an alkyl,    cycloalkyl, heterocyclyl or heteroaryl moiety then said moiety is    optionally further substituted by hydroxy, fluoro, chloro, cyano,    CF₃, OCF₃, (1-2C)alkyl, (1-2C)alkoxy, SO₂(1-2C)alkyl or NR_(e)R_(f)    (where R_(e) and R_(f) are each independently selected from    hydrogen, (1-3C)alkyl, (3-6C)cycloalkyl, or    (3-6C)cycloalkyl(1-2C)alkyl);-   or R₁₇ is a group having the formula:    -L³-L⁴-R₂₄-   L³ is absent or a linker group of the formula —[CR₂₅R₂₆]_(n)— in    which n is an integer selected from 1, 2, 3 or 4, and R₂₅ and R₂₆    are each independently selected from hydrogen or (1-2C)alkyl;-   L⁴ is absent or is selected from O, S, SO, SO₂, N(R₂₇), C(O), C(O)O,    OC(O), CH(OR₂₇), C(O)N(R₂₇), N(R₂₇)C(O), N(R₂₇)C(O)N(R₂₈),    S(O)₂N(R₂₇), or N(R₂₈)SO₂, wherein R₂₇ and R₂₈ are each    independently selected from hydrogen or (1-2C)alkyl; and-   R₂₄ is (1-6C)alkyl, aryl, aryl-(1-6C)alkyl, (3-6C)cycloalkyl,    (3-6C)cycloalkyl-(1-4C)alkyl, heteroaryl, heteroaryl-(1-4C)alkyl,    heterocyclyl, heterocyclyl-(1-4C)alkyl;-   (41) R₆ is halogeno, trifluoromethyl, trifluoromethoxy, cyano,    hydroxy, amino, carboxy, carbamoyl, sulphamoyl,-   or R₆ is a group of the formula:    -L¹-L²-R₁₇

wherein

-   L¹ is absent or a linker group of the formula —[CR₁₈R₁₉]_(n)— in    which n is an integer selected from 1 or 2, and R₁₈ and R₁₉ are both    hydrogen;-   L² is absent or is selected from O, S, SO, SO₂, N(R₂₀), C(O), C(O)O,    OC(O), CH(OR₂₀), C(O)N(R₂₀), N(R₂₀)C(O), N(R₂₀)C(O)N(R₂₁),    S(O)₂N(R₂₀), or N(R₂₀)SO₂, wherein R₂₀ and R₂₁ are each    independently selected from hydrogen or (1-2C)alkyl; and-   R₁₇ is (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6 membered    heteroaryl, or 3 to 8 membered heterocyclyl,-   and wherein R₁₇ is optionally further substituted by one or more    substituent groups independently selected from oxo, halo, cyano,    hydroxy, NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl, (1-5C)alkylsulphonyl, 3    to 6 membered heterocyclyl, 3 to 6 membered    heterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6    membered heteroaryl-(1-2C)alkyl, CONR₂₂R₂₃, and SO₂NR₂₂R₂₃; wherein    R₂₂ and R₂₃ are each independently selected from hydrogen,    (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or    R₂₂ and R₂₃ can be linked such that, together with the nitrogen atom    to which they are attached, they form a 4-6 membered heterocyclic    ring;-   and wherein when said substituent group comprises an alkyl,    cycloalkyl, heterocyclyl or heteroaryl moiety then said moiety is    optionally further substituted by hydroxy, fluoro, chloro, cyano,    CF₃, OCF₃, (1-2C)alkyl, (1-2C)alkoxy, SO₂(1-2C)alkyl or NR_(e)R_(f)    (where R_(e) and R_(f) are each independently selected from hydrogen    or (1-2C)alkyl);-   or R₁₇ is a group having the formula:    -L³-L⁴-R₂₄-   L³ is absent or a linker group of the formula —[CR₂₅R₂₆]_(n)— in    which n is an integer selected from 1 or 2, and R₂₅ and R₂₆ are each    hydrogen;-   L⁴ is absent or is selected from O, S, SO, SO₂, N(R₂₇), C(O), C(O)O,    OC(O), CH(OR₂₇), C(O)N(R₂₇), N(R₂₇)C(O), N(R₂₇)C(O)N(R₂₈),    S(O)₂N(R₂₇), or N(R₂₈)SO₂, wherein R₂₇ and R₂₈ are each    independently selected from hydrogen or (1-2C)alkyl; and-   R₂₄ is (1-2C)alkyl, aryl, aryl-(1-6C)alkyl, (3-6C)cycloalkyl, 5 or 6    membered heteroaryl, 3 to 8 membered heterocyclyl;-   (42) R₆ is a group of the formula:    -L¹-L²R₁₇

wherein

-   L¹ is absent or a linker group of the formula —[CR₁₈R₁₉]_(n)— in    which n is an integer selected from 1 or 2, and R₁₈ and R₁₉ are both    hydrogen;-   L² is absent or is selected from O, S, SO, SO₂, N(R₂₀), C(O), C(O)O,    OC(O), CH(OR₂₀), C(O)N(R₂₀), N(R₂₀)C(O), N(R₂₀)C(O)N(R₂₁),    S(O)₂N(R₂₀), or N(R₂₀)SO₂, wherein R₂₀ and R₂₁ are each    independently selected from hydrogen or (1-2C)alkyl; and-   R₁₇ is (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6 membered    heteroaryl, or 3 to 8 membered heterocyclyl,-   and wherein R₁₇ is optionally further substituted by one or more    substituent groups independently selected from oxo, halo, cyano,    hydroxy, NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl, (1-5C)alkylsulphonyl, 3    to 6 membered heterocyclyl, 3 to 6 membered    heterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6    membered heteroaryl-(1-2C)alkyl, CONR₂₂R₂₃, and SO₂NR₂₂R₂₃; wherein    R₂₂ and R₂₃ are each independently selected from hydrogen,    (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or    R₂₂ and R₂₃ can be linked such that, together with the nitrogen atom    to which they are attached, they form a 4-6 membered heterocyclic    ring;-   and wherein when said substituent group comprises an alkyl,    cycloalkyl, heterocyclyl or heteroaryl moiety then said moiety is    optionally further substituted by hydroxy, fluoro, chloro, cyano,    CF₃, OCF₃, (1-2C)alkyl, (1-2C)alkoxy, SO₂(1-2C)alkyl or NR_(e)R_(f)    (where R_(e) and R_(f) are each independently selected from hydrogen    or (1-2C)alkyl);-   or R₁₇ is a group having the formula:    -L³-L⁴-R₂₄-   L³ is absent or a linker group of the formula —[CR₂₅R₂₆]_(n)— in    which n is an integer selected from 1 or 2, and R₂₅ and R₂₆ are each    hydrogen;-   L⁴ is absent or is selected from O, S, SO, SO₂, N(R₂₇), C(O), C(O)O,    OC(O), CH(OR₂₇), C(O)N(R₂₇), N(R₂₇)C(O), N(R₂₇)C(O)N(R₂₈),    S(O)₂N(R₂₇), or N(R₂₈)SO₂, wherein R₂₇ and R₂₈ are each    independently selected from hydrogen or (1-2C)alkyl; and-   R₂₄ is (1-2C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6 membered    heteroaryl, 3 to 8 membered heterocyclyl;-   (43) R₆ is a group of the formula:    -L¹-L²-R₁₇

wherein

-   L¹ is absent or a linker group of the formula —[CR₁₈R₁₉]_(n)— in    which n is an integer selected from 1 or 2, and R₁₈ and R₁₉ are both    hydrogen;-   L² is absent or is selected from O, S, SO, SO₂, N(R₂₀), C(O), C(O)O,    OC(O), CH(OR₂₀), C(O)N(R₂₀), N(R₂₀)C(O), N(R₂₀)C(O)N(R₂₁),    S(O)₂N(R₂₀), or N(R₂₀)SO₂, wherein R₂₀ and R₂₁ are each    independently selected from hydrogen or (1-2C)alkyl; and-   R₁₇ is (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6 membered    heteroaryl, or 3 to 8 membered heterocyclyl,

and wherein R₁₇ is optionally further substituted by one or moresubstituent groups independently selected from oxo, halo, cyano,hydroxy, NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl, (1-5C)alkylsulphonyl, 3 to6 membered heterocyclyl, 3 to 6 membered heterocyclyl-(1-2C)alkyl, 5 or6 membered heteroaryl, 5 or 6 membered heteroaryl-(1-2C)alkyl,CONR₂₂R₂₃, and SO₂NR₂₂R₂₃; wherein R₂₂ and R₂₃ are each independentlyselected from hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl or(3-6C)cycloalkyl(1-2C)alkyl; or R₂₂ and R₂₃ can be linked such that,together with the nitrogen atom to which they are attached, they form a4-6 membered heterocyclic ring;

-   and wherein when said substituent group comprises an alkyl,    cycloalkyl, heterocyclyl or heteroaryl moiety then said moiety is    optionally further substituted by hydroxy, fluoro, chloro, cyano,    CF₃, OCF₃, (1-2C)alkyl, (1-2C)alkoxy, SO₂(1-2C)alkyl or NR_(e)R_(f)    (where R_(e) and R_(f) are each independently selected from hydrogen    or (1-2C)alkyl);-   or R₁₇ is a group having the formula:    -L³-L⁴-R₂₄-   L³ is absent;-   L⁴ is absent or is selected from O, S, SO, SO₂, N(R₂₇), C(O), C(O)O,    OC(O), CH(OR₂₇), C(O)N(R₂₇), N(R₂₇)C(O), N(R₂₇)C(O)N(R₂₈),    S(O)₂N(R₂₇), or N(R₂₈)SO₂, wherein R₂₇ and R₂₈ are each    independently selected from hydrogen or (1-2C)alkyl; and-   R₂₄ is (1-2C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6 membered    heteroaryl, 3 to 8 membered heterocyclyl;-   (44) R₆ is a group of the formula:    -L¹-L²-R₁₇

wherein

-   L¹ is absent;-   L² is absent or is selected from O, S, SO, SO₂, N(R₂₀), C(O), C(O)O,    OC(O), CH(OR₂₀), C(O)N(R₂₀), N(R₂₀)C(O), S(O)₂N(R₂₀), or N(R₂₀)SO₂,    wherein R₂₀ is selected from hydrogen or (1-2C)alkyl; and-   R₁₇ is (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6 membered    heteroaryl, or 3 to 8 membered heterocyclyl,-   and wherein R₁₇ is optionally further substituted by one or more    substituent groups independently selected from oxo, halo, cyano,    hydroxy, NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl, (1-5C)alkylsulphonyl, 3    to 6 membered heterocyclyl, 3 to 6 membered    heterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6    membered heteroaryl-(1-2C)alkyl, CONR₂₂R₂₃, and SO₂NR₂₂R₂₃; wherein    R₂₂ and R₂₃ are each independently selected from hydrogen or    (1-4C)alkyl;

and wherein when said substituent group comprises an alkyl, cycloalkyl,heterocyclyl or heteroaryl moiety then said moiety is optionally furthersubstituted by hydroxy, fluoro, chloro, cyano, CF₃, OCF₃, (1-2C)alkyl,(1-2C)alkoxy, SO₂(1-2C)alkyl or NR_(e)R_(f) (where R_(e) and R_(f) areeach independently selected from hydrogen or (1-2C)alkyl);

-   or R₁₇ is a group having the formula:    -L³-L⁴-R₂₄-   L³ is absent;-   L⁴ is absent or is selected from O, S, SO, SO₂, N(R₂₇), C(O), C(O)O,    OC(O), CH(OR₂₇), C(O)N(R₂₇), N(R₂₇)C(O), N(R₂₇)C(O)N(R₂₈),    S(O)₂N(R₂₇), or N(R₂₈)SO₂, wherein R₂₇ and R₂₈ are each    independently selected from hydrogen or (1-2C)alkyl; and-   R₂₄ is aryl, (3-6C)cycloalkyl, 5 or 6 membered heteroaryl, 3 to 8    membered heterocyclyl;-   (45) R₆ is a group of the formula:    -L¹-L²⁻R₁₇

wherein

-   L¹ is absent;-   L² is absent or is selected from O, S, SO, SO₂, N(R₂₀), C(O), C(O)O,    OC(O), CH(OR₂₀), C(O)N(R₂₀), N(R₂₀)C(O), S(O)₂N(R₂₀), or N(R₂₀)SO₂,    wherein R₂₀ is selected from hydrogen or (1-2C)alkyl; and-   R₁₇ is (1-6C)alkyl, phenyl, (3-6C)cycloalkyl, 5 or 6 membered    heteroaryl, or 3 to 6 membered heterocyclyl,-   and wherein R₁₇ is optionally further substituted by one or more    substituent groups independently selected from oxo, halo, cyano,    hydroxy, NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl, (1-4C)alkylsulphonyl, 3    to 6 membered heterocyclyl, 3 to 6 membered    heterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6    membered heteroaryl-(1-2C)alkyl, CONR₂₂R₂₃, and SO₂NR₂₂R₂₃; wherein    R₂₂ and R₂₃ are each independently selected from hydrogen or    (1-2C)alkyl;-   and wherein when said substituent group comprises an alkyl,    cycloalkyl, heterocyclyl or heteroaryl moiety then said moiety is    optionally further substituted by hydroxy, fluoro, chloro, cyano,    CF₃, OCF₃, (1-2C)alkyl, (1-2C)alkoxy, SO₂(1-2C)alkyl or NR_(e)R_(f)    (where R_(e) and R_(f) are each independently selected from hydrogen    or methyl);-   or R₁₇ is a group having the formula:    -L³-L⁴-R₂₄-   L³ is absent;-   L⁴ is absent or is selected from O, S, SO, SO₂, N(R₂₇), C(O), C(O)O,    OC(O), CH(OR₂₇), C(O)N(R₂₇), N(R₂₇)C(O), N(R₂₇)C(O)N(R₂₈),    S(O)₂N(R₂₇), or N(R₂₈)SO₂, wherein R₂₇ and R₂₈ are each    independently selected from hydrogen or (1-2C)alkyl; and-   R₂₄ is 3 to 8 membered heterocyclyl;-   (46) R₆ is halogeno, trifluoromethyl, trifluoromethoxy, cyano,    hydroxy, amino, carboxy, carbamoyl, sulphamoyl,-   or R₆ is a group of the formula:    -L¹-L²-R₁₇

wherein

-   L¹ is absent or a linker group of the formula —[CR₁₈R₁₉]_(n)— in    which n is an integer selected from 1 or 2, and R₁₅ and R₁₉ are each    independently selected from hydrogen or methyl;-   L² is absent or is selected from O, S, SO, SO₂, N(R₂₀), C(O), C(O)O,    OC(O), CH(OR₂₀), C(O)N(R₂₀), N(R₂₀)C(O), N(R₂₀)C(O)N(R₂₁),    S(O)₂N(R₂₀), or N(R₂₀)SO₂, wherein R₂₀ and R₂₁ are each    independently selected from hydrogen or (1-2C)alkyl; and-   R₁₇ is (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6 membered    heteroaryl, or 3 to 8 membered heterocyclyl,-   and wherein R₁₇ is optionally further substituted by one or more    substituent groups independently selected from oxo, halo, cyano,    nitro, hydroxy, NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl,    (3-8C)cycloalkyl, (3-8C)cycloalkyl-(1-3C)alkyl, (1-5C)alkanoyl,    (1-5C)alkylsulphonyl, 3 to 6 membered heterocyclyl, 3 to 6 membered    heterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6    membered heteroaryl-(1-2C)alkyl, CONR₂₂R₂₃, and SO₂NR₂₂R₂₃; wherein    R₂₂ and R₂₃ are each independently selected from hydrogen,    (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or    R₂₂ and R₂₃ can be linked such that, together with the nitrogen atom    to which they are attached, they form a 4-6 membered heterocyclic    ring;-   and wherein when said substituent group comprises an alkyl,    cycloalkyl, heterocyclyl or heteroaryl moiety then said moiety is    optionally further substituted by hydroxy, fluoro, chloro, cyano,    CF₃, OCF₃, (1-2C)alkyl, (1-2C)alkoxy, SO₂(1-2C)alkyl or NR_(e)R_(f)    (where R_(e) and R_(f) are each independently selected from    hydrogen, (1-3C)alkyl, (3-6C)cycloalkyl, or    (3-6C)cycloalkyl(1-2C)alkyl);-   (47) R₆ is halogeno, trifluoromethyl, trifluoromethoxy, cyano,    hydroxy, amino, carboxy, carbamoyl, sulphamoyl,-   or R₆ is a group of the formula:    -L¹-L²-R₁₇

wherein

-   L¹ is absent or a linker group of the formula —[CR₁₈R₁₉]_(n)— in    which n is an integer selected from 1 or 2, and R₁₈ and R₁₉ are both    hydrogen;-   L² is absent or is selected from O, S, SO, SO₂, N(R₂₀), C(O), C(O)O,    OC(O), CH(OR₂₀), C(O)N(R₂₀), N(R₂₀)C(O), N(R₂₀)C(O)N(R₂₁),    S(O)₂N(R₂₀), or N(R₂₀)SO₂, wherein R₂₀ and R₂₁ are each    independently selected from hydrogen or (1-2C)alkyl; and-   R₁₇ is (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6 membered    heteroaryl, or 3 to 8 membered heterocyclyl,-   and wherein R₁₇ is optionally further substituted by one or more    substituent groups independently selected from oxo, halo, cyano,    hydroxy, NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl, (1-5C)alkylsulphonyl, 3    to 6 membered heterocyclyl, 3 to 6 membered    heterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6    membered heteroaryl-(1-2C)alkyl, CONR₂₂R₂₃, and SO₂NR₂₂R₂₃; wherein    R₂₂ and R₂₃ are each independently selected from hydrogen,    (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or    R₂₂ and R₂₃ can be linked such that, together with the nitrogen atom    to which they are attached, they form a 4-6 membered heterocyclic    ring;-   and wherein when said substituent group comprises an alkyl,    cycloalkyl, heterocyclyl or heteroaryl moiety then said moiety is    optionally further substituted by hydroxy, fluoro, chloro, cyano,    CF₃, OCF₃, (1-2C)alkyl, (1-2C)alkoxy, SO₂(1-2C)alkyl or NR_(e)R_(f)    (where R_(e) and R_(f) are each independently selected from hydrogen    or (1-2C)alkyl);-   (48) R₆ is a group of the formula:    -L¹-L²-R₁₇

wherein

-   L¹ is absent or a linker group of the formula —[CR₁₈R₁₉]_(n)— in    which n is an integer selected from 1 or 2, and R₁₈ and R₁₉ are both    hydrogen;-   L² is absent or is selected from O, S, SO, SO₂, N(R₂₀), C(O), C(O)O,    OC(O), CH(OR₂₀), C(O)N(R₂₀), N(R₂₀)C(O), N(R₂₀)C(O)N(R₂₁),    S(O)₂N(R₂₀), or N(R₂₀)SO₂, wherein R₂₀ and R₂₁ are each    independently selected from hydrogen or (1-2C)alkyl; and-   R₁₇ is (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6 membered    heteroaryl, or 3 to 8 membered heterocyclyl,-   and wherein R₁₇ is optionally further substituted by one or more    substituent groups independently selected from oxo, halo, cyano,    hydroxy, NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl, (1-5C)alkylsulphonyl, 3    to 6 membered heterocyclyl, 3 to 6 membered    heterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6    membered heteroaryl-(1-2C)alkyl, CONR₂₂R₂₃, and SO₂NR₂₂R₂₃; wherein    R₂₂ and R₂₃ are each independently selected from hydrogen,    (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or    R₂₂ and R₂₃ can be linked such that, together with the nitrogen atom    to which they are attached, they form a 4-6 membered heterocyclic    ring;-   and wherein when said substituent group comprises an alkyl,    cycloalkyl, heterocyclyl or heteroaryl moiety then said moiety is    optionally further substituted by hydroxy, fluoro, chloro, cyano,    CF₃, OCF₃, (1-2C)alkyl, (1-2C)alkoxy, SO₂(1-2C)alkyl or NR_(e)R_(f)    (where R_(e) and R_(f) are each independently selected from hydrogen    or (1-2C)alkyl);-   (49) R₆ is a group of the formula:    -L¹-L²-R₁₇

wherein

-   L¹ is absent or a linker group of the formula —[CR₁₈R₁₉]_(n)— in    which n is an integer selected from 1 or 2, and R₁₈ and R₁₉ are both    hydrogen;-   L² is absent or is selected from O, S, SO, SO₂, N(R₂₀), C(O), C(O)O,    OC(O), CH(OR₂₀), C(O)N(R₂₀), N(R₂₀)C(O), N(R₂₀)C(O)N(R₂₁),    S(O)₂N(R₂₀), or N(R₂₀)SO₂, wherein R₂₀ and R₂₁ are each    independently selected from hydrogen or (1-2C)alkyl; and-   R₁₇ is (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6 membered    heteroaryl, or 3 to 8 membered heterocyclyl,-   and wherein R₁₇ is optionally further substituted by one or more    substituent groups independently selected from oxo, halo, cyano,    hydroxy, NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl, (1-5C)alkylsulphonyl, 3    to 6 membered heterocyclyl, 3 to 6 membered    heterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6    membered heteroaryl-(1-2C)alkyl, CONR₂₂R₂₃, and SO₂NR₂₂R₂₃; wherein    R₂₂ and R₂₃ are each independently selected from hydrogen,    (1-4C)alkyl or (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; or    R₂₂ and R₂₃ can be linked such that, together with the nitrogen atom    to which they are attached, they form a 4-6 membered heterocyclic    ring;

and wherein when said substituent group comprises an alkyl, cycloalkyl,heterocyclyl or heteroaryl moiety then said moiety is optionally furthersubstituted by hydroxy, fluoro, chloro, cyano, CF₃, OCF₃, (1-2C)alkyl,(1-2C)alkoxy, SO₂(1-2C)alkyl or NR_(e)R_(f) (where R_(e) and R_(f) areeach independently selected from hydrogen or (1-2C)alkyl);

-   (50) R₆ is a group of the formula:    -L¹-L²-R₁₇

wherein

-   L¹ is absent;-   L² is absent or is selected from O, S, SO, SO₂, N(R₂₀), C(O), C(O)O,    OC(O), CH(OR₂₀), C(O)N(R₂₀), N(R₂₀)C(O), S(O)₂N(R₂₀), or N(R₂₀)SO₂,    wherein R₂₀ is selected from hydrogen or (1-2C)alkyl; and-   R₁₇ is (1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6 membered    heteroaryl, or 3 to 8 membered heterocyclyl,-   and wherein R₁₇ is optionally further substituted by one or more    substituent groups independently selected from oxo, halo, cyano,    hydroxy, NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl, (1-5C)alkylsulphonyl, 3    to 6 membered heterocyclyl, 3 to 6 membered    heterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6    membered heteroaryl-(1-2C)alkyl, CONR₂₂R₂₃, and SO₂NR₂₂R₂₃; wherein    R₂₂ and R₂₃ are each independently selected from hydrogen or    (1-4C)alkyl;-   and wherein when said substituent group comprises an alkyl,    cycloalkyl, heterocyclyl or heteroaryl moiety then said moiety is    optionally further substituted by hydroxy, fluoro, chloro, cyano,    CF₃, OCF₃, (1-2C)alkyl, (1-2C)alkoxy, SO₂(1-2C)alkyl or NR_(e)R_(f)    (where R_(e) and R_(f) are each independently selected from hydrogen    or (1-2C)alkyl);-   (51) R₆ is a group of the formula:    -L¹-L²-R₁₇

wherein

-   L¹ is absent;-   L² is absent or is selected from O, S, SO, SO₂, N(R₂₀), C(O), C(O)O,    OC(O), CH(OR₂₀), C(O)N(R₂₀), N(R₂₀)C(O), S(O)₂N(R₂₀), or N(R₂₀)SO₂,    wherein R₂₀ is selected from hydrogen or (1-2C)alkyl; and-   R₁₇ is (1-6C)alkyl, phenyl, (3-6C)cycloalkyl, 5 or 6 membered    heteroaryl, or 3 to 6 membered heterocyclyl,-   and wherein R₁₇ is optionally further substituted by one or more    substituent groups independently selected from oxo, halo, cyano,    hydroxy, NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl, (1-4C)alkylsulphonyl, 3    to 6 membered heterocyclyl, 3 to 6 membered    heterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6    membered heteroaryl-(1-2C)alkyl, CONR₂₂R₂₃, and SO₂NR₂₂R₂₃; wherein    R₂₂ and R₂₃ are each independently selected from hydrogen or    (1-2C)alkyl;-   and wherein when said substituent group comprises an alkyl,    cycloalkyl, heterocyclyl or heteroaryl moiety then said moiety is    optionally further substituted by hydroxy, fluoro, chloro, cyano,    CF₃, OCF₃, (1-2C)alkyl, (1-2C)alkoxy, SO₂(1-2C)alkyl or NR_(e)R_(f)    (where R_(e) and R_(f) are each independently selected from hydrogen    or methyl);-   (52) R₆ is a group of the formula:    -L¹-L²-R₁₇

wherein

-   L¹ is absent;-   L² is absent; and-   R₁₇ is a 5 or 6 membered heteroaryl comprising 1, 2 or 3 nitrogen    atoms,-   and wherein R₁₇ is optionally further substituted by one or more    substituent groups independently selected from halo, cyano, hydroxy,    NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl, (1-5C)alkylsulphonyl, 3 to 6    membered heterocyclyl, 3 to 6 membered heterocyclyl-(1-2C)alkyl, 5    or 6 membered heteroaryl, 5 or 6 membered heteroaryl-(1-2C)alkyl,    CONR₂₂R₂₃, and SO₂NR₂₂R₂₃; wherein R₂₂ and R₂₃ are each    independently selected from hydrogen or (1-4C)alkyl;-   (53) R₆ is a group of the formula:    -L¹-L²-R₁₇

wherein

-   L¹ is absent;-   L² is absent; and-   R₁₇ is a 5 membered heteroaryl comprising 1, 2 or 3 nitrogen atoms;-   and wherein R₁₇ is optionally further substituted by one or more    substituent groups independently selected from halo, cyano, hydroxy,    NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl, (1-5C)alkylsulphonyl, 3 to 6    membered heterocyclyl, 3 to 6 membered heterocyclyl-(1-2C)alkyl, 5    or 6 membered heteroaryl, 5 or 6 membered heteroaryl-(1-2C)alkyl,    CONR₂₂R₂₃, and SO₂NR₂₂R₂₃; wherein R₂₂ and R₂₃ are each    independently selected from hydrogen or (1-4C)alkyl;-   (54) R₈ and R₉ are each independently selected from hydrogen,    (1-6C)alkyl, (3-9C)cycloalkyl, (3-6C)cycloalkyl-(1-2C)alkyl, phenyl,    3 to 9 membered heterocyclyl, 3 to 9 membered    heterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6    membered heteroaryl-(1-2C)alkyl, and wherein R₈ and R₉ are    optionally further substituted by one or more substituents selected    from hydroxy, fluoro, chloro, cyano, CF₃, OCF₃, (1-2C)alkyl or    (1-2C)alkoxy;-   (55) R₈ and R₉ are each independently selected from hydrogen,    (1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-2C)alkyl, 3 to 6    membered heterocyclyl, 3 to 6 membered heterocyclyl-(1-2C)alkyl, and    wherein R₈ and R₉ are optionally further substituted by one or more    substituents selected from hydroxy, fluoro, chloro, cyano, CF₃,    OCF₃, methyl or methoxy;-   (56) R₇ and R₁₀ are independently selected from hydrogen,    (1-4C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-2C)alkyl;-   (57) R₇ and R₁₀ are independently selected from hydrogen or    (1-4C)alkyl;-   (58) R₇ and R₁₀ are independently selected from hydrogen or    (1-2C)alkyl;-   (59) R₇ and R₁₀ are independently selected from hydrogen or methyl;-   (60) R₇ and R₁₀ are hydrogen;-   (61) W is N;-   (62) W is C—R₃;-   (63) W is C—CH₃.

As stated above, X can only be N when Z is N and W may only be N when Xand Z are both N. Accordingly, the compounds of formula I may have oneof the structures Ia, Ib, Ic or Id shown below:

or a pharmaceutically acceptable salt or solvate thereof.

Suitably, the compounds of formula I have one or the structures 1b, 1cor 1d above, or a pharmaceutically acceptable salt or solvate thereof.

In an embodiment, the compound of the invention is a compound of formulaIa above, wherein R₁, R₃, R₄ and Ar each have any one of the definitionsset out herein, or a pharmaceutically acceptable salt or solvatethereof.

In an embodiment, the compound of the invention is a compound of formulaIb, wherein R₁, R₃, R₄ and Ar each have any one of the definitions setout herein, or a pharmaceutically acceptable salt or solvate thereof.

In an embodiment, the compound of the invention is a compound of formulaIc, wherein R₁, R₃, R₄ and Ar each have any one of the definitions setout herein, or a pharmaceutically acceptable salt or solvate thereof.

In an embodiment, the compound of the invention is a compound of formulaId, wherein R₁, R₄ and Ar each have any one of the definitions set outherein, or a pharmaceutically acceptable salt or solvate thereof.

Suitably, the compounds of formula I have the structural formula Ia orIc, especially structural formula Ic, or a pharmaceutically acceptablesalt or solvate thereof.

Suitably, R₁ is as defined in any one of paragraphs (5) to (17) above.

Suitably, R₃ is as defined in any one of paragraphs (18) to (23) above.

Suitably, R₄ is as defined in any one of paragraphs (24) to (28) above.

Suitably, Ar is as defined in any one of paragraphs (29) to (33) above.

Suitably, R₅ is as defined in any one of paragraphs (34) to (39) above.

Suitably, R₆ is as defined in any one of paragraphs (40) to (53) above.

Suitably, R₈ and R₉ are as defined in any one of paragraphs (54) to (55)above.

Suitably, R₇ and R₁₀ are as defined in any one of paragraphs (56) to(60) above.

Suitably, W is as defined in any one of paragraphs (61) to (63) above.

In an embodiment, the compound is a compound of formula I, Ia, Ib or Icas defined herein wherein R₃ is H and R₁, R₄, and Ar each have any oneof the definitions set out herein, or a pharmaceutically acceptable saltor solvate thereof.

In an embodiment, the compound is a compound of formula I, Ia, Ib, Ic orId as defined herein wherein R₄ is H and R₁, R₃, and Ar each have anyone of the definitions set out herein, or a pharmaceutically acceptablesalt or solvate thereof.

In an embodiment, the compound is a compound of formula I, Ia, Ib or Icas defined herein wherein R₃ and R₄ are H, and R₁ and Ar each have anyone of the definitions set out herein, or a pharmaceutically acceptablesalt or solvate thereof.

In an embodiment, the compound is a compound of formula Ia, Ib, Ic or Idas defined herein wherein A₃ is CH and R₁, R₃, R₄, R₅, R₆, A₁ and A₂each have any one of the definitions set out herein, or apharmaceutically acceptable salt or solvate thereof.

In an embodiment, the compound is a compound of formula Ia, Ib, Ic or Idas defined herein wherein A₃ is CH; R₃ and R₄ are both H; and R₁, R₅,R₆, A₁ and A₂ each have any one of the definitions set out herein, or apharmaceutically acceptable salt or solvate thereof.

In an embodiment, the compound is a compound of formula Ia, Ib, Ic or Idas defined herein wherein

-   A₃ is CH;-   R₃ and R₄ are both H;-   R₁ is as defined in any one of paragraphs (5) to (15) above;-   R₅ is as defined in any one of paragraphs (30) to (35) above;-   R₆ is as defined in any one of paragraphs (36) to (44) above;-   both of A₁ and A₂ are CH or one of A₁ and A₂ is CH and the other is    N;-   or a pharmaceutically acceptable salt or solvate thereof.

In an embodiment, the compound is a compound of formula Ia, Ib, Ic or Idas defined herein wherein

-   A₃ is CH;-   R₃ and R₄ are both H;-   R₂ is as defined in any one of paragraphs (10) to (16) above;-   R₅ is as defined in any one of paragraphs (32) to (35) above;-   R₆ is as defined in any one of paragraphs (36) to (44) above;-   both of A₁ and A₂ are CH or one of A₁ and A₂ is CH and the other is    N;-   or a pharmaceutically acceptable salt or solvate thereof.

In an embodiment, the compound is a compound of formula I, Ia, Ib, Ic orId as defined herein wherein Ar is as defined in either paragraph (28)or (29) above, and R₁, R₃ and R₄ each have any one of the definitionsset out herein, or a pharmaceutically acceptable salt or solvatethereof.

In an embodiment, the compound is a compound of formula I, Ib, Ic or Idas defined herein wherein Ar is as defined in either paragraph (28) or(29) above, and R₁, R₃ and R₄ each have any one of the definitions setout herein, or a pharmaceutically acceptable salt or solvate thereof.

In an embodiment, the compound is a compound of formula I, Ia, Ib, Ic orId as defined herein in which Ar has the formula:

wherein:

-   (i) all of A₁, A₂ and A₃ are CH; or-   (ii) A₂ and A₃ are both CH and A₁ is N;-   R₅ is methoxy or chloro; and-   R₁, R₃, R₄ and R₆ each have any one of the definitions set out    herein;-   or a pharmaceutically acceptable salt or solvate thereof.

In an embodiment, the compound is a compound of formula I, Ia, Ib, Ic orId (especially formula Ic) as defined herein before in which Ar has theformula:

wherein:

-   (i) all of A₁, A₂ and A₃ are CH; or-   (ii) A₃ is CH and one of A₁ or A₂ is N;-   R₅ is (1-2C)alkoxy, OCF₃, or OCHF₂;-   R₃ is hydrogen or methyl;-   R₄ is hydrogen;-   R₁ is as defined in any one of paragraphs (16) or (17) above; and-   R₆ is as defined in any one of paragraphs (52) or (53) above;-   or a pharmaceutically acceptable salt or solvate thereof.

In an embodiment, the compound is a compound of formula I, Ia, Ib, Ic orId (especially formula Ic) as defined herein before in which Ar has theformula:

wherein:

-   all of A₁, A₂ and A₃ are CH;-   R₅ is (1-2C)alkoxy or OCHF₂;-   R₃ is hydrogen or methyl;-   R₄ is hydrogen;-   R₁ is as defined in paragraph (16) or (17) above; and-   R₆ is as defined in any one of paragraphs (52) or (53) above;-   or a pharmaceutically acceptable salt or solvate thereof.

Particular compounds of the present invention include any one of thecompounds exemplified in the present application, or a pharmaceuticallyacceptable salt or solvate thereof, and, in particular, any one of thefollowing:

-   5-(furan-2-yl)-N-(4-methoxyphenyl)isoquinolin-3-amine;-   N-(4-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine;-   N-(2-methoxy-4-((1-methylpiperidin-4-yl)oxy)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine;-   N-(2,4-dimethoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine;-   3-chloro-N,N-dimethyl-4-((5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)benzamide;-   3-methoxy-N,N-dimethyl-4-((5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)benzamide;-   (3-methoxy-4-((5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone;-   N-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine;-   (3-chloro-4-((5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone;-   (3-methoxy-4-((5-(pyridin-3-yl)isoquinolin-3-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone;-   N-(4-(3,5-dimethylisoxazol-4-yl)-2-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine;-   (3-methoxy-4-((8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N-(2-chloro-4-(1-methyl-1H-imidazol-5-yl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine;-   (3-methoxy-4-((5-(pyrimidin-5-yl)isoquinolin-3-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone;-   N-(2-methoxy-4-(1-methyl-1H-imidazol-5-yl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine;-   (4-((5-(1,5-dimethyl-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)-3-methoxyphenyl)(3-methoxyazetidin-1-yl)methanone;-   (3-methoxy-4-((5-(1-methyl-1H-pyrazol-3-yl)isoquinolin-3-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone;-   N-(2-chloro-4-(1,2-dimethyl-1H-imidazol-5-yl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine;-   N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-phenylpyrido[3,4-d]pyrimidin-2-amine;-   8-cyclopropyl-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenylpyrido[3,4-d]pyrimidin-2-amine;-   N-(2-methoxy-5-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine;-   (3-methoxy-4-((5-(1-methyl-1H-pyrazol-5-yl)isoquinolin-3-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone;-   (4-((5-(1,3-dimethyl-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)-3-methoxyphenyl)(3-methoxyazetidin-1-yl)methanone;-   (4-((5-(1-isopropyl-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)-3-methoxyphenyl)(3-methoxyazetidin-1-yl)methanone;-   4-((5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)-N-(1-methylpiperidin-4-yl)-3-(trifluoromethoxy)benzamide;-   (4-((5-(3,5-dimethylisoxazol-4-yl)isoquinolin-3-yl)amino)-3-methoxyphenyl)(3-methoxyazetidin-1-yl)methanone;-   (3-methoxy-4-((5-(1-methyl-1H-imidazol-5-yl)isoquinolin-3-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine;-   tert-butyl    4-(4-(3-((2-methoxy-4-(3-methoxyazetidine-1-carbonyl)phenyl)amino)isoquinolin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate;-   (3-methoxy-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone;-   (3-methoxy-4-((5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone;-   (3-methoxy-4-((5-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone;-   N8,N8-diethyl-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N8-cyclopentyl-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   (4-((5-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)-3-methoxyphenyl)(3-methoxyazetidin-1-yl)methanone;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-2,6-naphthyridin-3-amine;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N8-cyclohexyl-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(3-methylpyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2-amine;-   8-(3,3-difluoropyrrolidin-1-yl)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine;-   N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-2,6-naphthyridin-3-amine;-   N8-(cyclopropylmethyl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine;-   N8-cyclopentyl-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-methylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N-(2-isopropoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N-(2-(2-methoxyethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N8-isopentyl-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-morpholinopyrido[3,4-d]pyrimidin-2-amine;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyrimidin-2-amine;-   8-(3,3-difluoroazetidin-1-yl)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(2-methylpyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N8-isobutyl-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   8-(cyclohexylthio)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(6-azaspiro[3.4]octan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N8-cyclohexyl-N2-(2-methoxy-4-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   8-(1-ethyl-1H-pyrazol-4-yl)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine;-   8-(1-isopropyl-1H-pyrazol-4-yl)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(3-methoxyazetidin-1-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N1-(cyclopropylmethyl)-N7-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-2,6-naphthyridine-1,7-diamine;-   N1-cyclohexyl-N7-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-2,6-naphthyridine-1,7-diamine;-   N8-cyclohexyl-N2-(4-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N8-(cyclopropylmethyl)-N2-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N8-cyclohexyl-N2-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N8-(cyclopropylmethyl)-N2-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N8-(cyclohexylmethyl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   2-(4-(4-((8-(cyclohexylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)-1H-pyrazol-1-yl)ethanol;-   8-(cyclopropylmethoxy)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine;-   1-((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)-2-methylpropan-2-ol;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(oxetan-3-ylmethyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N8-(3,3-dimethylbutan-2-yl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   3-((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)-2,2-dimethylpropan-1-ol;-   N2-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-6-morpholinopyridin-3-yl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-6-(methylsulfonyl)pyridin-3-yl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(1-methyl-1H-imidazol-5-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N8-(1-cyclopropylethyl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   2-(4-(3-methoxy-4-((8-((tetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)ethanol;-   N2-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   (R)-N8-(3,3-dimethylbutan-2-yl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   (S)-N8-(3,3-dimethylbutan-2-yl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(tetrahydrofuran-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-((tetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   1-(2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyrrolidin-3-ol;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-methyl-N8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N8-(tert-butyl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(1-methylcyclohexyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   8-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-morpholinophenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N8-(2,2-difluoropropyl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N8-(3-methoxy-2,2-dimethylpropyl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)methyl)cyclobutanol;-   8-chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(2-ethyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(4-(1-methyl-1H-pyrazol-4-yl)-2-(trifluoromethoxy)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-methylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8,N8-dimethylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)-2-methylpropane-2-sulfinamide;-   N2-(2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-((3-methyloxetan-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(piperidin-1-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)-2-methylpropane-2-sulfonamide;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(oxetan-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   (1-(3-methoxy-4-((8-(neopentylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)(morpholino)methanone;-   N2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   1-(((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)methyl)cyclopropanol;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(1-methylpiperidin-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   2-((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)-2-methylpropan-1-ol;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(oxetan-2-ylmethyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-chloro-4-morpholinophenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine-   N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-8-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-((3-methyloxetan-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-N8-(2-methoxy-2-methylpropyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   2-((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)ethanol;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(2-methoxyethyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   1-((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)propan-2-ol;-   2-((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)propan-1-ol;-   N2-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   4-(2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)thiomorpholine    1,1-dioxide;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(6-oxa-2-azaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)azetidine-3-carbonitrile;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(2-oxa-7-azaspiro[4.4]nonan-7-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(2-oxa-6-azaspiro[3.5]nonan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N8-((3-fluorooxetan-3-yl)methyl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-chloro-2-methoxyphenyl)-8-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N-(2,4-dichlorophenyl)-8-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   4-((8-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)-3-methoxybenzonitrile;-   N-(2-chloro-4-(methylsulfonyl)phenyl)-8-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N-(2-chloro-4-(pyrimidin-5-yl)phenyl)-8-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N-(2-chloro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-8-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;-   6-cyclopropyl-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   2-((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)propane-1,3-diol;-   3-methoxy-2-((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)propan-1-ol;-   (3-(((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)methyl)oxetan-3-yl)methanol;-   (S)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   (R)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(4-chloro-2-fluorophenyl)-8-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;-   4-((8-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)-3-chlorobenzonitrile;-   N2-(2-methoxy-4-(1-(2-methoxyethyl)-2-methyl-1H-imidazol-5-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-5-methylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-5-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(2-methylmorpholino)pyrido[3,4-d]pyrimidin-2-amine;-   (4-(3-methoxy-4-((8-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)-1-methyl-1H-pyrazol-5-yl)methanol;-   (4-(3-methoxy-4-((8-(((3-methyltetrahydrofuran-3-yl)methyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)-1-methyl-1H-pyrazol-5-yl)methanol;-   N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-4-(1-(2-methoxyethyl)-2-methyl-1H-imidazol-5-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(1-(2-methoxyethyl)-2-methyl-1H-imidazol-5-yl)phenyl)-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   8-(3,6-dihydro-2H-pyran-4-yl)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine;-   N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-6-(1-methyl-1H-tetrazol-5-yl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(6-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxypyridin-3-yl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(1-(tetrahydrofuran-3-yl)ethyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(4-methoxypiperidin-1-yl)pyrido[3,4-d]pyrimidin-2-amine;-   1-(2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)piperidine-4-carbonitrile;-   N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(4-(methylsulfonyl)piperazin-1-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-(2-methoxy-2-methylpropyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-8-(6-oxa-2-azaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N2-(6-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxypyridin-3-yl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(6-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxypyridin-3-yl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-6-(1-methyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-6-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   (3-methoxy-4-((8-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone;-   3-methoxy-4-((8-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)-N,N-dimethylbenzamide;-   (3-methoxy-4-((8-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)(4-methylpiperazin-1-yl)methanone;-   (1-(2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyrrolidin-3-yl)methanol;-   (1-(2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)piperidin-3-yl)methanol;-   (4-(2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)morpholin-2-yl)methanol;-   N2-(2-(difluoromethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-(difluoromethoxy)-4-fluorophenyl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(4-(1-ethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   (3-methoxy-4-((8-(neopentylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone;-   N2-(2-methoxy-4-(tetrahydro-2H-pyran-4-yl)phenyl)-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(4-chloro-2-(difluoromethoxy)phenyl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-5-methyl-N8-((3-methyloxetan-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-5-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;-   N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-5-methyl-8-(6-oxa-2-azaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-2-amine;-   N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;-   N2-(2-(difluoromethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(2-methoxy-2-methylpropyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;-   (4-(3-methoxy-4-((8-((2-methoxy-2-methylpropyl)amino)-6-methylpyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)-1-methyl-1H-pyrazol-5-yl)methanol;-   or a pharmaceutically acceptable salt or solvate thereof.

The various functional groups and substituents making up the compoundsof the present invention are typically chosen such that the molecularweight of the compound does not exceed 1000. More usually, the molecularweight of the compound will be less than 750, for example less than 700,or less than 650, or less than 600, or less than 550. More preferably,the molecular weight is less than 525 and, for example, is 500 or less.

Suitable or preferred features of any compounds of the present inventionmay also be suitable features of any other aspect.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic,formic, citric or maleic acid. In addition a suitable pharmaceuticallyacceptable salt of a compound of the invention which is sufficientlyacidic is an alkali metal salt, for example a sodium or potassium salt,an alkaline earth metal salt, for example a calcium or magnesium salt,an ammonium salt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

Compounds that have the same molecular formula but differ in the natureor sequence of bonding of their atoms or the arrangement of their atomsin space are termed “isomers”. Isomers that differ in the arrangement oftheir atoms in space are termed “stereoisomers”. Stereoisomers that arenot mirror images of one another are termed “diastereomers” and thosethat are non-superimposable mirror images of each other are termed“enantiomers”. When a compound has an asymmetric center, for example, itis bonded to four different groups, a pair of enantiomers is possible.An enantiomer can be characterized by the absolute configuration of itsasymmetric center and is described by the R- and S-sequencing rules ofCahn and Prelog, or by the manner in which the molecule rotates theplane of polarized light and designated as dextrorotatory orlevorotatory (i.e., as (+) or (−)-isomers respectively). A chiralcompound can exist as either individual enantiomer or as a mixturethereof. A mixture containing equal proportions of the enantiomers iscalled a “racemic mixture”.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art (see discussion in Chapter 4 of “Advanced OrganicChemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001),for example by synthesis from optically active starting materials or byresolution of a racemic form. Some of the compounds of the invention mayhave geometric isomeric centres (E- and Z-isomers). It is to beunderstood that the present invention encompasses all optical,diastereoisomers and geometric isomers and mixtures thereof that possessMps1 kinase inhibitory activity.

The present invention also encompasses compounds of the invention asdefined herein which comprise one or more isotopic substitutions. Forexample, H may be in any isotopic form, including ¹H, ²H(D), and ³H (T);C may be in any isotopic form, including ¹²C, ¹³C, and ¹⁴C; and O may bein any isotopic form, including ¹⁶O and ¹⁸O; and the like.

It is also to be understood that certain compounds of the invention mayexist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms that possess Mps1 kinase inhibitory activity.

It is also to be understood that certain compounds of the invention mayexhibit polymorphism, and that the invention encompasses all such formsthat possess Mps1 kinase inhibitory activity.

Compounds of the invention may exist in a number of different tautomericforms and references to compounds of the invention include all suchforms. For the avoidance of doubt, where a compound can exist in one ofseveral tautomeric forms, and only one is specifically described orshown, all others are nevertheless embraced by compounds of theinvention. Examples of tautomeric forms include keto-, enol-, andenolate-forms, as in, for example, the following tautomeric pairs:keto/enol (illustrated below), imine/enamine, amide/imino alcohol,amidine/amidine, nitroso/oxime, thioketone/enethiol, andnitro/aci-nitro.

Compounds of the invention containing an amine function may also formN-oxides. A reference herein to a compound of the formula I thatcontains an amine function also includes the N-oxide. Where a compoundcontains several amine functions, one or more than one nitrogen atom maybe oxidised to form an N-oxide. Particular examples of N-oxides are theN-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containingheterocycle. N-Oxides can be formed by treatment of the correspondingamine with an oxidizing agent such as hydrogen peroxide or a per-acid(e.g. a peroxycarboxylic acid), see for example Advanced OrganicChemistry, by Jerry March, 4^(th) Edition, Wiley Interscience, pages.More particularly, N-oxides can be made by the procedure of L. W. Deady(Syn. Comm. 1977, 7, 509-514) in which the amine compound is reactedwith m-chloroperoxybenzoic acid (MCPBA), for example, in an inertsolvent such as dichloromethane.

The compounds of the invention may be administered in the form of apro-drug which is broken down in the human or animal body to release acompound of the invention. A pro-drug may be used to alter the physicalproperties and/or the pharmacokinetic properties of a compound of theinvention. A pro-drug can be formed when the compound of the inventioncontains a suitable group or substituent to which a property-modifyinggroup can be attached. Examples of pro-drugs include in vivo cleavableester derivatives that may be formed at a carboxy group or a hydroxygroup in a compound of the invention and in-vivo cleavable amidederivatives that may be formed at a carboxy group or an amino group in acompound of the invention.

Accordingly, the present invention includes those compounds of theformula I as defined hereinbefore when made available by organicsynthesis and when made available within the human or animal body by wayof cleavage of a pro-drug thereof. Accordingly, the present inventionincludes those compounds of the formula I that are produced by organicsynthetic means and also such compounds that are produced in the humanor animal body by way of metabolism of a precursor compound, that is acompound of the formula I may be a synthetically-produced compound or ametabolically-produced compound.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I is one that is based on reasonable medical judgement as beingsuitable for administration to the human or animal body withoutundesirable pharmacological activities and without undue toxicity.

Various forms of pro-drug have been described, for example in thefollowing documents:—

-   a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder,    et al. (Academic Press, 1985);-   b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985);-   c) A Textbook of Drug Design and Development, edited by    Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and    Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991);-   d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992);-   e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285    (1988);-   f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984);-   g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”,    A.C.S. Symposium Series, Volume 14; and-   h) E. Roche (editor), “Bioreversible Carriers in Drug Design”,    Pergamon Press, 1987.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I that possesses a carboxy group is, for example, an in vivocleavable ester thereof. An in vivo cleavable ester of a compound of theformula I containing a carboxy group is, for example, a pharmaceuticallyacceptable ester which is cleaved in the human or animal body to producethe parent acid. Suitable pharmaceutically acceptable esters for carboxyinclude C₁₋₆alkyl esters such as methyl, ethyl and tert-butyl,C₁₋₆alkoxymethyl esters such as methoxymethyl esters,C₁₋₆alkanoyloxymethyl esters such as pivaloyloxymethyl esters,3-phthalidyl esters, C₃₋₈cycloalkylcarbonyloxy-C₁₋₆alkyl esters such ascyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters,2-oxo-1,3-dioxolenylmethyl esters such as5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters andC₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl esters such as methoxycarbonyloxymethyland 1-methoxycarbonyloxyethyl esters.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I that possesses a hydroxy group is, for example, an in vivocleavable ester or ether thereof. An in vivo cleavable ester or ether ofa compound of the formula I containing a hydroxy group is, for example,a pharmaceutically acceptable ester or ether which is cleaved in thehuman or animal body to produce the parent hydroxy compound. Suitablepharmaceutically acceptable ester forming groups for a hydroxy groupinclude inorganic esters such as phosphate esters (includingphosphoramidic cyclic esters). Further suitable pharmaceuticallyacceptable ester forming groups for a hydroxy group includeC₁₋₁₀alkanoyl groups such as acetyl, benzoyl, phenylacetyl andsubstituted benzoyl and phenylacetyl groups, C₁₋₁₀alkoxycarbonyl groupssuch as ethoxycarbonyl, N,N-(C₁₋₆)₂carbamoyl, 2-dialkylaminoacetyl and2-carboxyacetyl groups. Examples of ring substituents on thephenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl,N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and4-(C₁₋₄alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptableether forming groups for a hydroxy group include α-acyloxyalkyl groupssuch as acetoxymethyl and pivaloyloxymethyl groups.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I that possesses a carboxy group is, for example, an in vivocleavable amide thereof, for example an amide formed with an amine suchas ammonia, a C₁₋₄alkylamine such as methylamine, a (C₁₋₄alkyl)₂ aminesuch as dimethylamine, N-ethyl-N-methylamine or diethylamine, aC₁₋₄alkoxy-C₂₋₄alkylamine such as 2-methoxyethylamine, aphenyl-C₁₋₄alkylamine such as benzylamine and amino acids such asglycine or an ester thereof.

A suitable pharmaceutically acceptable pro-drug of a compound of theformula I that possesses an amino group is, for example, an in vivocleavable amide derivative thereof. Suitable pharmaceutically acceptableamides from an amino group include, for example an amide formed withC₁₋₁₀alkanoyl groups such as an acetyl, benzoyl, phenylacetyl andsubstituted benzoyl and phenylacetyl groups. Examples of ringsubstituents on the phenylacetyl and benzoyl groups include aminomethyl,N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl,piperazin-1-ylmethyl and 4-(C₁₋₄alkyl)piperazin-1-ylmethyl.

The in vivo effects of a compound of the formula I may be exerted inpart by one or more metabolites that are formed within the human oranimal body after administration of a compound of the formula I. Asstated hereinbefore, the in vivo effects of a compound of the formula Imay also be exerted by way of metabolism of a precursor compound (apro-drug).

It shall also be appreciated that compounds of formula I may also becovalently linked (at any suitable position) to other groups such as,for example, solubilising moieties (for example, PEG polymers), moietiesthat enable them to be bound to a solid support (such as, for example,biotin-containing moieties), and targeting ligands (such as antibodiesor antibody fragments).

Synthesis

In the description of the synthetic methods described below and in thereferenced synthetic methods that are used to prepare the staringmaterials, it is to be understood that all proposed reaction conditions,including choice of solvent, reaction atmosphere, reaction temperature,duration of the experiment and workup procedures, can be selected by aperson skilled in the art.

It is understood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the molecule must becompatible with the reagents and reaction conditions utilised.

Necessary starting materials may be obtained by standard procedures oforganic chemistry. The preparation of such starting materials isdescribed in conjunction with the following representative processvariants and within the accompanying Examples. Alternatively necessarystarting materials are obtainable by analogous procedures to thoseillustrated which are within the ordinary skill of an organic chemist.

It will be appreciated that during the synthesis of the compounds of theinvention in the processes defined below, or during the synthesis ofcertain starting materials, it may be desirable to protect certainsubstituent groups to prevent their undesired reaction. The skilledchemist will appreciate when such protection is required, and how suchprotecting groups may be put in place, and later removed.

For examples of protecting groups see one of the many general texts onthe subject, for example, ‘Protective Groups in Organic Synthesis’ byTheodora Green (publisher: John Wiley & Sons). Protecting groups may beremoved by any convenient method described in the literature or known tothe skilled chemist as appropriate for the removal of the protectinggroup in question, such methods being chosen so as to effect removal ofthe protecting group with the minimum disturbance of groups elsewhere inthe molecule.

Thus, if reactants include, for example, groups such as amino, carboxyor hydroxy it may be desirable to protect the group in some of thereactions mentioned herein.

By way of example, a suitable protecting group for an amino oralkylamino group is, for example, an acyl group, for example an alkanoylgroup such as acetyl, an alkoxycarbonyl group, for example amethoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, anarylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroylgroup, for example benzoyl. The deprotection conditions for the aboveprotecting groups necessarily vary with the choice of protecting group.Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonylgroup or an aroyl group may be removed by, for example, hydrolysis witha suitable base such as an alkali metal hydroxide, for example lithiumor sodium hydroxide. Alternatively an acyl group such as atert-butoxycarbonyl group may be removed, for example, by treatment witha suitable acid as hydrochloric, sulfuric or phosphoric acid ortrifluoroacetic acid and an arylmethoxycarbonyl group such as abenzyloxycarbonyl group may be removed, for example, by hydrogenationover a catalyst such as palladium-on-carbon, or by treatment with aLewis acid for example BF₃.OEt₂. A suitable alternative protecting groupfor a primary amino group is, for example, a phthaloyl group which maybe removed by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium, sodium hydroxide or ammonia. Alternatively anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

Resins may also be used as a protecting group.

In a particular aspect, the present invention provides a method ofsynthesising a compound of the formula I, or a pharmaceuticallyacceptable salt or solvate thereof, the method comprising:

-   a) reacting a compound of formula A:

wherein W, X, Z, R₁ and R₄ each have any one of the meanings as definedhereinbefore, and LG_(A) is a suitable leaving group;

-   with a compound of formula B:    H₂N—Ar  Formula B    wherein Ar is as defined herein; and-   b) optionally thereafter, and if necessary:-   i) removing any protecting groups present;-   ii) converting the compound formula I into another compound of    formula I; and/or-   iii) forming a pharmaceutically acceptable salt or solvate thereof.

LG_(A) may be any suitable leaving group. Suitably LG_(A) is a halogenor any other suitable leaving group (e.g. trifluoromethylsulphonateetc.). Suitably LG_(A) may be chlorine, bromine ortrifluoromethylsulphonate.

Suitably the coupling reaction between compound A and compound B takesplace in the presence of a suitable solvent. Any suitable solvent orsolvent mixture may be used for this reaction. A person skilled in theart will know how to select suitable solvents or solvent mixtures foruse in these reactions. Examples of suitable solvents include DMA,1,4-dioxane, toluene, DMF, tBuOH, THF and H₂O.

A person skilled in the art will be able to select appropriate reactionconditions to use in order to facilitate this reaction. Suitably, thereaction is carried out in anhydrous conditions and in the presence ofan inert atmosphere, such as argon or nitrogen. The reaction may also becarried out an elevated temperature, such as, for example, within therange of 80 to 160° C. or, more suitably 100 to 160° C. (depending onthe solvent utilised), for a suitable time period of, for example, 2hours to 7 days, or more suitably 2 to 10 hours either thermally orunder microwave irradiation.

Suitably the coupling reaction between compound A and compound B takesplace in the presence of a catalyst, suitably a palladium-derivedcatalyst, such as Pd or Pd₂(dba)₃ or by using an acid catalysis, such astrifluoroacetic acid.

Suitably the coupling reaction between compound A and compound B takesplace in the presence of an organophosphorus compound, suitably anorganophosphorus compound which serves as a suitable ligand to thecatalyst. The organophosphorus compound may suitably be aphosphine-derivative, such as Xantphos.

Suitably the coupling reaction between compound A and compound B takesplace in the presence of a base, for example a metal carbonate, such ascesium carbonate, or metal hydrides, such as sodium hydride.

The compound of formula A can be prepared by processes known in the art,and suitably by the processes described herein with reference to theexamples.

The compound of formula B can be prepared by processes known in the art,and suitably by the processes described herein with reference to theexamples.

A racemic compound of formula I may be separated using suitable chiralseparation chromatography to furnish the desired enantiomers.

In another aspect, the present invention provides a method ofsynthesising a compound of the formula I, or a pharmaceuticallyacceptable salt or solvate thereof, the method comprising:

-   a) reacting a compound of formula C:

wherein W, X, Z, R₁ and R₄ each have any one of the meanings as definedhereinbefore;

-   with a compound of formula B as defined hereinbefore, or a compound    of formula D:    HC(O)HN—Ar  Formula D    wherein Ar is as defined herein; and-   b) optionally thereafter, and if necessary:-   i) removing any protecting groups present;-   ii) converting the compound formula I into another compound of    formula I; and/or-   iii) forming a pharmaceutically acceptable salt or solvate thereof.

Suitably the coupling reaction between compound C and compound B or Dtakes place in the presence of a suitable solvent. Any suitable solventor solvent mixture may be used for this reaction. A person skilled inthe art will know how to select suitable solvents or solvent mixturesfor use in these reactions. Examples of suitable solvents include THF,TFE (1,2,3-trifluoroethanol) or DMF.

A person skilled in the art will be able to select appropriate reactionconditions to use in order to facilitate this reaction. Suitably, thereaction is carried out in anhydrous conditions and in the presence ofan inert atmosphere, such as argon or nitrogen. The reaction may also becarried out an elevated temperature, such as, for example, within therange of 30 to 170° C. or, more suitably 30 to 50° C. for compounds offormula D and 120 to 170 50° C. for compounds of formula B (depending onthe solvent utilised), for a suitable time period of, for example, 2hours to 7 days, or more suitably 2 to 10 hours either thermally orunder microwave irradiation.

Suitably the coupling reaction between compound C and compounds B or Dtakes place in the presence of a catalyst, suitably a palladium-derivedcatalyst, such as Pd or Pd₂(dba)₃ or by using an acid catalysis, such astrifluoroacetic acid.

Suitably the coupling reaction between compound C and compounds B or Dtakes place in the presence of an organophosphorus compound, suitably anorganophosphorus compound which serves as a suitable ligand to thecatalyst. The organophosphorus compound may suitably be aphosphine-derivative, such as Xantphos.

Suitably the coupling reaction between compound C and compounds B or Dtakes place in the presence of a base, for example a metal carbonate,such as cesium carbonate, or metal hydrides, such as sodium hydride.

The compound of formula C can be prepared by processes known in the art,and suitably by the processes described herein with reference to theexamples.

The compound of formula D can be prepared by processes known in the art,and suitably by the processes described herein with reference to theexamples.

In another aspect, the present invention provides a method ofsynthesising a compound of the formula I, or a pharmaceuticallyacceptable salt or solvate thereof, the method comprising:

-   a) reacting a compound of formula E:

wherein W, X, Z, Ar and R₄ each have any one of the meanings as definedhereinbefore, and LG_(A) is a suitable leaving group as hereinbeforedefined;

-   with a compound of formula F:    H₂N—R₁  Formula F-   or R₁BX₂, wherein R₁ is as defined herein, and BX₂ represents    boronic acids (e.g. B(OH)₂), tetrafluoroborates (e.g. R₁BF₃ ⁻), or    pinacol esters;-   or R₁SH, wherein R₁ is as defined herein, and-   b) optionally thereafter, and if necessary:-   i) removing any protecting groups present;-   ii) converting the compound formula I into another compound of    formula I; and/or-   iii) forming a pharmaceutically acceptable salt or solvate thereof.

As described above, LG_(A) may be any suitable leaving group. SuitablyLG_(A) is a halogen or any other suitable leaving group (e.g.trifluoromethylsulphonate etc.). Suitably LG_(A) may be chlorine orbromine.

Suitably the coupling reaction between compound E and compound F takesplace in the presence of a suitable solvent. Any suitable solvent orsolvent mixture may be used for this reaction. A person skilled in theart will know how to select suitable solvents or solvent mixtures foruse in these reactions. Examples of suitable solvents include dioxane,DMA, NMP, THF, or TFE.

A person skilled in the art will be able to select appropriate reactionconditions to use in order to facilitate this reaction. Suitably, thereaction is carried out in anhydrous conditions and in the presence ofan inert atmosphere, such as argon or nitrogen. The reaction may also becarried out an elevated temperature, such as, for example, within therange of 100 to 140° C. (depending on the solvent utilised), for asuitable time period of, for example, 2 hours to 7 days, or moresuitably 2 to 10 hours either thermally or under microwave irradiation.

Suitably the coupling reaction between compound E and compound F takesplace in the presence of a catalyst, suitably a palladium-derivedcatalyst, such as Pd or Pd₂(dba)₃, Pd(PPh₃)₄ or Pd(dppf)Cl₂ or by usingan acid catalysis, such as trifluoroacetic acid.

Suitably the coupling reaction between compound E and compound F takesplace in the presence of an organophosphorus compound, suitably anorganophosphorus compound which serves as a suitable ligand to thecatalyst. The organophosphorus compound may suitably be aphosphine-derivative, such as Xantphos or DavePhos.

Suitably the coupling reaction between compound E and compound F takesplace in the presence of a base, for example a metal carbonate, such ascesium carbonate, or metal hydrides, such as sodium hydride.

The compound of formula E can be prepared by processes known in the artand/or by the processes described herein with reference to the examples.

The compound of formula F can be prepared by processes known in the art,and/or by the processes described herein with reference to the examples.

The resultant compound of formula I can be isolated and purified usingtechniques well known in the art.

The processes defined herein may further comprise the step of subjectingthe compound of formula I to a salt exchange, particularly in situationswhere the compound of formula I is formed as a mixture of different saltforms. The salt exchange suitably comprises immobilising the compound offormula I on a suitable solid support or resin, and eluting thecompounds with an appropriate acid to yield a single salt of thecompound of formula I.

In a further aspect of the invention, there is provided a compound offormula I obtainable by any one of the processes defined herein.

In a further aspect of the invention, there is provided a compound offormula I obtained by any one of the processes defined herein.

In a further aspect of the invention, there is provided a compound offormula I directly obtained by any one of the processes defined herein.

By way of example, particular synthetic schemes by which compounds ofthe invention can be prepared are shown below in Schemes 1 to 12:

The product of Scheme 12 is then reacted to form a compound of formula Iusing the last two steps of previous Scheme 11.

In schemes 1 to 9, R₁ is suitably aryl or heteroaryl, but may also bealkyl or alkenyl. BX2 represents boronic acids (B(OH)₂),tetrafluoroborates (R1BF₃ ⁻), or pinacol esters, e.g.

Biological Activity

The following biological assays may be used to measure thepharmacological effects of the compounds of the present invention.

Measurement of Inhibition of MPS1 Kinase

The enzyme reaction (total volume 10 μl) was carried out in black384-well low volume plates containing full length MPS1 (12.5 nM or 3nM), fluorescent labelled peptide [known as H236, which has thesequence: 5FAM-DHTGFLTEYVATR-CONH₂] (5 μM), ATP (10 μM), either DMSO (1%v/v) or the test compound (in the range 0.25 nM-100 μM in 1% DMSO) andassay buffer (50 mM HEPES (pH 7.0), 0.02% NaN₃, 0.01% BSA, 0.1 mMOrthovandate, 10 μM MgCl₂, 1 μM DTT, Roche protease inhibitor). Thereaction was carried out for 60 min at room temperature and stopped bythe addition of buffer (10 μl) containing 20 mM EDTA, 0.05% (v/v)Brij-35, in 0.1M HEPES-buffered saline (Free acid, Sigma, UK). The platewas read on a Caliper EZ reader II (Caliper Life Sciences).

The reader provides a Software package (‘Reviewer’) which converts thepeak heights into % conversion by measuring both product and substratepeak and also allows selection of control well which represent 0% and100% inhibition, respectively. The % inhibition of the compounds iscalculated relative to the means of selected control wells. IC₅₀s aredetermined by testing the compounds at a range of concentrations from0.25 nM-100 μM. The % inhibitions at each concentration are then fittedto a 4 parameter logistic fit:y=(a+((b−a)/(1+((c/x^d))))where a=asym min, b=asym max, c=IC₅₀ and d=hill coefficient

In general, activity possessed by compounds of the formula I, may bedemonstrated in the inhibition assay by an IC₅₀ value of less than 15μM. Suitably compounds have an IC₅₀ value of less than 10 μM, suitablyless than 1 μM, suitably less than 0.1 μM, and suitably less than 0.01μM (i.e. less than 10 nM).

The activities of compounds of the invention in the above assay areshown in the accompanying example section.

Pharmaceutical Compositions

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the inventionas defined hereinbefore, or a pharmaceutically acceptable salt orsolvate thereof, in association with a pharmaceutically acceptablediluent or carrier.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular,intraperitoneal or intramuscular dosing or as a suppository for rectaldosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

An effective amount of a compound of the present invention for use intherapy of proliferative disease is an amount sufficient tosymptomatically relieve in a warm-blooded animal, particularly a humanthe symptoms of infection, to slow the progression of infection, or toreduce in patients with symptoms of infection the risk of getting worse.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, forexample from 1 to 30 mg) compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition.

The size of the dose for therapeutic or prophylactic purposes of acompound of the formula I will naturally vary according to the natureand severity of the conditions, the age and sex of the animal or patientand the route of administration, according to well known principles ofmedicine.

In using a compound of the invention for therapeutic or prophylacticpurposes it will generally be administered so that a daily dose in therange, for example, 0.1 mg/kg to 75 mg/kg body weight is received, givenif required in divided doses. In general lower doses will beadministered when a parenteral route is employed. Thus, for example, forintravenous or intraperitoneal administration, a dose in the range, forexample, 0.1 mg/kg to 30 mg/kg body weight will generally be used.Similarly, for administration by inhalation, a dose in the range, forexample, 0.05 mg/kg to 25 mg/kg body weight will be used. Oraladministration may also be suitable, particularly in tablet form.Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of acompound of this invention.

Therapeutic Uses and Applications

In one aspect, the present invention provides a compound of Formula I,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein for use in therapy.

The compounds of the invention are capable of inhibiting Mps1 kinaseactivity. Thus, in another aspect, the present invention provides amethod of inhibiting Mps1 kinase activity in a cell, the methodcomprising administering to said cell compound of formula I as definedherein, or a pharmaceutically acceptable salt or solvate thereof.

In a further aspect, the present invention provides a method ofinhibiting Mps1 kinase in vitro or in vivo, said method comprisingcontacting a cell with an effective amount of a compound, or apharmaceutically acceptable salt or solvate thereof, as defined herein.

In another aspect, the present invention provides a method of inhibitingMps1 kinase activity in a human or animal subject in need of suchinhibition, the method comprising administering to said subject aneffective amount of a compound of formula I as defined herein, or apharmaceutically acceptable salt or solvate thereof.

In another aspect, the present invention provides a compound of formulaI as defined herein, or a pharmaceutically acceptable salt or solvatethereof for use in the treatment of disease or condition associated withMps1 kinase activity.

In another aspect, the present invention provides the use of a compoundof formula I as defined herein, or a pharmaceutically acceptable salt orsolvate thereof, in the manufacture of a medicament for use in thetreatment of disease or condition associated with Mps1 kinase activity.

In yet another aspect, the present invention provides a method oftreating a proliferative disorder in a human or animal subject, themethod comprising administering to said subject a therapeuticallyacceptable amount of a compound of formula I as defined herein, or apharmaceutically acceptable salt or solvate thereof.

In yet another aspect, the present invention provides a compound offormula I as defined herein, or a pharmaceutically acceptable salt orsolvate thereof, for use in the treatment of a proliferative disorder.

In yet another aspect, the present invention provides the use of acompound of formula I as defined herein, or a pharmaceuticallyacceptable salt or solvate thereof, in the manufacture of a medicamentfor use in the treatment of a proliferative disorder.

The term “proliferative disorder” are used interchangeably herein andpertain to an unwanted or uncontrolled cellular proliferation ofexcessive or abnormal cells which is undesired, such as, neoplastic orhyperplasticgrowth, whether in vitro or in vivo. Examples ofproliferative conditions include, but are not limited to, pre-malignantand malignant cellular proliferation, including but not limited to,malignant neoplasms and tumours, cancers, leukemias, psoriasis, bonediseases, fibroproliferative disorders (e.g., of connective tissues),and atherosclerosis. Any type of cell may be treated, including but notlimited to, lung, colon, breast, ovarian, prostate, liver, pancreas,brain, and skin.

The anti-proliferative effects of the compounds of the present inventionhave particular application in the treatment of human cancers by virtueof their Mps1 kinase inhibitory properties.

The anti-cancer effect may arise through one or more mechanisms,including but not limited to, the regulation of cell proliferation, theinhibition of angiogenesis (the formation of new blood vessels), theinhibition of metastasis (the spread of a tumour from its origin), theinhibition of invasion (the spread of tumour cells into neighbouringnormal structures), or the promotion of apoptosis (programmed celldeath).

Therefore, in another aspect, the present invention provides a compound,or a pharmaceutically acceptable salt or solvate thereof, or apharmaceutical composition as defined herein for use in the treatment ofcancer.

In yet another aspect, the present invention provides the use of acompound, or a pharmaceutically acceptable salt or solvate thereof, asdefined herein in the manufacture of a medicament for use in thetreatment of cancer.

In yet another aspect, the present invention provides a method oftreating cancer in a patient in need of such treatment, said methodcomprising administering to said patient a therapeutically effectiveamount of a compound, or a pharmaceutically acceptable salt or solvatethereof, or a pharmaceutical composition as defined herein.

The invention further provides a method of treatment of the human oranimal body, the method comprising administering to a subject in need oftreatment a therapeutically-effective amount of an active compound,preferably in the form of a pharmaceutical composition.

Routes of Administration

The compounds of the invention or pharmaceutical composition comprisingthe active compound may be administered to a subject by any convenientroute of administration, whether systemically/peripherally or topically(ie. at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g, byingestion); buccal; sublingual; transdermal (including, e.g., by apatch, plaster, etc.); transmucosal (including, e.g., by a patch,plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., byeyedrops); pulmonary (e.g., by inhalation or insufflation therapy using,e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., bysuppository or enema); vaginal (e.g., by pessary); parenteral, forexample, by injection, including subcutaneous, intradermal,intramuscular, intravenous, intraarterial, intracardiac, intrathecal,intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal,intratracheal, subcuticular, intraarticular, subarachnoid, andintrasternal; by implant of a depot or reservoir, for example,subcutaneously or intramuscularly.

Combination Therapies

The antiproliferative treatment defined hereinbefore may be applied as asole therapy or may involve, in addition to the compound of theinvention, conventional surgery or radiotherapy or chemotherapy. Suchchemotherapy may include one or more of the following categories ofanti-tumour agents:—

-   (i) other antiproliferative/antineoplastic drugs and combinations    thereof, as used in medical oncology, such as alkylating agents (for    example cis-platin, oxaliplatin, carboplatin, cyclophosphamide,    nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide    and nitrosoureas); antimetabolites (for example gemcitabine and    antifolates such as fluoropyrimidines like 5-fluorouracil and    tegafur, raltitrexed, methotrexate, cytosine arabinoside, and    hydroxyurea); antitumour antibiotics (for example anthracyclines    like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin,    idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic    agents (for example vinca alkaloids like vincristine, vinblastine,    vindesine and vinorelbine and taxoids like taxol and taxotere and    polokinase inhibitors); and topoisomerase inhibitors (for example    epipodophyllotoxins like etoposide and teniposide, amsacrine,    topotecan and camptothecin);-   (ii) cytostatic agents such as antioestrogens (for example    tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and    iodoxyfene), antiandrogens (for example bicalutamide, flutamide,    nilutamide and cyproterone acetate), LHRH antagonists or LHRH    agonists (for example goserelin, leuprorelin and buserelin),    progestogens (for example megestrol acetate), aromatase inhibitors    (for example as anastrozole, letrozole, vorazole and exemestane) and    inhibitors of 5α-reductase such as finasteride;-   (iii) anti-invasion agents [for example c-Src kinase family    inhibitors like    4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline    (AZD0530; International Patent Application WO 01/94341),    N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole-5-carboxamide    (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and    bosutinib (SKI-606), and metalloproteinase inhibitors like    marimastat, inhibitors of urokinase plasminogen activator receptor    function or antibodies to Heparanase];-   (iv) inhibitors of growth factor function: for example such    inhibitors include growth factor antibodies and growth factor    receptor antibodies (for example the anti-erbB2 antibody trastuzumab    [Herceptin™], the anti-EGFR antibody panitumumab, the anti-erbB1    antibody cetuximab [Erbitux, C225] and any growth factor or growth    factor receptor antibodies disclosed by Stern et al. Critical    reviews in oncology/haematology, 2005, Vol. 54, pp 11-29); such    inhibitors also include tyrosine kinase inhibitors, for example    inhibitors of the epidermal growth factor family (for example EGFR    family tyrosine kinase inhibitors such as    N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine    (gefitinib, ZD1839),    N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine    (erlotinib, OSI-774) and    6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine    (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib);    inhibitors of the hepatocyte growth factor family; inhibitors of the    insulin growth factor family; inhibitors of the platelet-derived    growth factor family such as imatinib and/or nilotinib (AMN107);    inhibitors of serine/threonine kinases (for example Ras/Raf    signalling inhibitors such as farnesyl transferase inhibitors, for    example sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib    (SCH66336)), inhibitors of cell signalling through MEK and/or AKT    kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase    inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF    receptor (insulin-like growth factor) kinase inhibitors; aurora    kinase inhibitors (for example AZD1152, PH739358, VX-680, MLN8054,    R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase    inhibitors such as CDK2 and/or CDK4 inhibitors;-   (v) antiangiogenic agents such as those which inhibit the effects of    vascular endothelial growth factor, [for example the anti-vascular    endothelial cell growth factor antibody bevacizumab (Avastin™) and    for example, a VEGF receptor tyrosine kinase inhibitor such as    vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248),    axitinib (AG-013736), pazopanib (GW 786034) and    4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline    (AZD2171; Example 240 within WO 00/47212), compounds such as those    disclosed in International Patent Applications WO97/22596, WO    97/30035, WO 97/32856 and WO 98/13354 and compounds that work by    other mechanisms (for example linomide, inhibitors of integrin αvβ3    function and angiostatin)];-   (vi) vascular damaging agents such as Combretastatin A4 and    compounds disclosed in International Patent Applications WO    99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO    02/08213;-   (vii) an endothelin receptor antagonist, for example zibotentan    (ZD4054) or atrasentan;-   (viii) antisense therapies, for example those which are directed to    the targets listed above, such as ISIS 2503, an anti-ras antisense;-   (ix) gene therapy approaches, including for example approaches to    replace aberrant genes such as aberrant p53 or aberrant BRCA1 or    BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such    as those using cytosine deaminase, thymidine kinase or a bacterial    nitroreductase enzyme and approaches to increase patient tolerance    to chemotherapy or radiotherapy such as multi-drug resistance gene    therapy; and-   (x) immunotherapy approaches, including for example ex-vivo and    in-vivo approaches to increase the immunogenicity of patient tumour    cells, such as transfection with cytokines such as interleukin 2,    interleukin 4 or granulocyte-macrophage colony stimulating factor,    approaches to decrease T-cell anergy, approaches using transfected    immune cells such as cytokine-transfected dendritic cells,    approaches using cytokine-transfected tumour cell lines and    approaches using anti-idiotypic antibodies.

Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment. Such combination products employ the compounds of thisinvention within the dosage range described hereinbefore and the otherpharmaceutically-active agent within its approved dosage range.

According to this aspect of the invention there is provided acombination suitable for use in the treatment of a cancer (for example acancer involving a solid tumour) comprising a compound of the inventionas defined hereinbefore, or a pharmaceutically acceptable salt orsolvate thereof, and another anti-tumour agent.

According to this aspect of the invention there is provided acombination suitable for use in the treatment of a cancer (for example acancer involving a solid tumour) comprising a compound of the inventionas defined hereinbefore, or a pharmaceutically acceptable salt orsolvate thereof, and any one of the anti-tumour agents listed under(i)-(ix) above.

In a further aspect of the invention there is provided a compound of theinvention or a pharmaceutically acceptable salt or solvate thereof, incombination with an anti-tumour agent selected from one listed under(i)-(ix) herein above.

Herein, where the term “combination” is used it is to be understood thatthis refers to simultaneous, separate or sequential administration. Inone aspect of the invention “combination” refers to simultaneousadministration. In another aspect of the invention “combination” refersto separate administration. In a further aspect of the invention“combination” refers to sequential administration. Where theadministration is sequential or separate, the delay in administering thesecond component should not be such as to lose the beneficial effect ofthe combination.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of the invention,or a pharmaceutically acceptable salt or solvate thereof in combinationwith an anti-tumour agent selected from one listed under (i)-(ix) hereinabove, in association with a pharmaceutically acceptable diluent orcarrier.

EXAMPLES

Commercially available starting materials, reagents and dry solventswere used as supplied. Flash column chromatography was performed usingMerck silica gel 60 (0.025-0.04 mm). Column chromatography was alsoperformed on a FlashMaster personal unit using isolute Flash silicacolumns or a Biotage SP1 purification system using Merck or BiotageFlash silica cartridges. Preparative TLC was performed on Analtech orMerck plates. Ion exchange chromatography was performed using acidicIsolute Flash SCX-II columns, Isolute Si-carbonate columns or basicisolute Flash NH₂ columns.

Where a preparative HPLC method is used, the following conditions apply:

Grad15mins20mIsLipo:

Reagents:

HPLC grade solvents, formic acid, or alternative eluent modifiers werepurchased from Sigma Aldrich (Poole, UK) unless otherwise stated.

Instrumentation:

450 uL standard injections (with needle rinse) of the sample, at 10mg/mL concentration in MeOH, were made onto a Phenomenex Gemini column(10 μm, 250×21.2 mm, C18, Phenomenex, Torrance, USA)

Chromatographic separation at room temperature was carried out usingGilson GX-281 Liquid Handler system combined with a Gilson 322 HPLC pump(Gilson, Middleton, USA) over a 15 minute gradient elution from 40:60 to100:0 methanol:water (both modified with 0.1% formic acid) at a flowrate of 20 mL/min.

UV-Vis spectra were acquired at 254 nm on a Gilson 156 UV-Vis detector(Gilson, Middleton, USA).

Collection was triggered by UV signal, and collected using a GilsonGX-281 Liquid Handler system (Gilson, Middleton, USA).

Raw data was processed using Gilson Trilution Software.

Where an LCMS method is used, the following conditions apply:

LCT method: LC/MS analysis was also performed on a Waters Alliance 2795Separations Module and Waters 2487 dual wavelength absorbance detectorcoupled to a Waters/Micromass LCt time of flight mass spectrometer withESI source. Analytical separation was carried out at 30° C. either on aMerck Chromolith SpeedROD column (RP-18e, 50×4.6 mm) using a flow rateof 2 mL/min in a 4 minute gradient elution with detection at 254 nm oron a Merck Purospher STAR column (RP-18e, 30×4 mm) using a flow rate of1.5 mL/min in a 4 minute gradient elution with detection at 254 nm. Themobile phase was a mixture of methanol (solvent A) and water (solvent B)both containing formic acid at 0.1%. Gradient elution was as follows:1:9 (A/B) to 9:1 (A/B) over 2.25 min, 9:1 (A/B) for 0.75 min, and thenreversion back to 1:9 (A/B) over 0.3 min, finally 1:9 (A/B) for 0.2 min

Where an LCMS/HRMS method is used, the following conditions apply:

Agilent ToF Method: LC/MS and HRMS analysis was performed on an Agilent1200 series HPLC and diode array detector coupled to a 6210 time offlight mass spectrometer with dual multimode APCI/ESI source.

Analytical separation was carried out at 30° C. on a Merck PurospherSTAR column (RP-18e, 30×4 mm) using a flow rate of 1.5 mL/min in a 4minute gradient elution with detection at 254 nm. The mobile phase was amixture of methanol (solvent A) and water containing formic acid at 0.1%(solvent B). Gradient elution was as follows: 1:9 (A/B) to 9:1 (A/B)over 2.5 min, 9:1 (A/B) for 1 min, and then reversion back to 1:9 (A/B)over 0.3 min, finally 1:9 (A/B) for 0.2 min.

The references used for HRMS analysis were: caffeine [M+H]⁺ 195.087652;hexakis (2,2-difluoroethoxy)phosphazene [M+H]⁺ 622.02896; andhexakis(1H,1H,3H-tetrafluoropentoxy)phosphazene [M+H]⁺ 922.009798.

Routine LCMS was performed using the LCT method whereas HRMS data wererecorded using the Agilent ToF method.

Example 1(4-((5-(1-(2-(Dimethylamino)ethyl)-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)-3-methoxyphenyl)(3-methoxyazetidin-1-yl)methanone

Method 1

A suspension of2-(4-(3-chloroisoquinolin-5-yl)-1H-pyrazol-1-yl)-N,N-dimethylethanamine(Preparation 1, 10 mg, 0.033 mmol),(4-amino-3-methoxyphenyl)(3-methoxyazetidin-1-yl)methanone (Preparation28, 15.7 mg, 0.066 mmol), xantphos (11.5 mg, 0.02 mmol), Pd₂(dba)₃ (3mg, 0.003 mmol) and Cs₂CO₃ (87 mg, 0.27 mmol) in toluene/DMF (3/1 mL)was stirred at 160° C. under microwave irradiation for 2 hours. Thereaction mixture was filtered, diluted with NaCl solution and extractedwith EtOAc. The organic layer was purified by SCX-2 column eluting with2M NH₃/MeOH and concentrated in vacuo. The residue was purified byBiotage silica gel column chromatography eluting with 0-4% MeOH in EtOAcfollowed by preparative HPLC to afford the title compound (5 mg, 30%).

¹H NMR (500 MHz, CDCl₃): δ 9.07 (d, J=0.8 Hz, 1H), 8.06 (d, J=8.3 Hz,1H), 7.90 (s, 1H), 7.84 (dt, J=8.1, 1.0 Hz, 1H), 7.81 (d, J=0.8 Hz, 1H),7.61-7.55 (m, 2H), 7.52 (d, J=1.1 Hz, 1H), 7.38 (dd, J=8.2, 7.0 Hz, 1H),7.34 (d, J=1.9 Hz, 1H), 7.27-7.20 (m, 1H), 4.68 (t, J=6.4 Hz, 2H),4.55-4.35 (m, 2H), 4.31-4.25 (m, 2H), 4.15-4.05 (m, 1H), 3.98 (s, 3H),3.42 (t, J=6.4 Hz, 2H), 3.35 (s, 3H), 2.60 (s, 6H).

LCMS (ESI) Rt=1.92 minutes MS m/z 501 [M+H]⁺

MPS1 IC50 (μM): 0.061

The following Examples were prepared according to Method 1 (Example 1)above using the appropriate chloroisoquinoline and the appropriateaniline as described. The crude reaction residues were purified as aboveor according to one of the following methods:

-   Method A: Biotage silica gel column chromatography eluting with    between 0-6% MeOH/EtOAc.-   Method B: Biotage silica gel column chromatography eluting with    EtOAc.-   Method C: Biotage silica gel column chromatography eluting with    0-12% MeOH/EtOAc.-   Method D: Biotage silica gel column chromatography eluting with 60%    EtOAc/cyclohexane followed by preparative HPLC.-   Method E: Biotage silica gel column chromatography eluting with    0-30% MeOH/EtOAc followed by preparative HPLC.-   Method F: Biotage silica gel column chromatography eluting with    60-100% EtOAc/cyclohexane.-   Method G: Biotage silica gel column chromatography eluting with 40%    EtOAc/cyclohexane.

MPS1 Example IC50 No Name/Structure Data (μM)  2

¹H NMR (500 MHz, CDCl₃): δ 9.06 (d, J = 0.9 Hz, 1H), 8.06 (d, J = 8.3Hz, 1H), 7.82 (dt, J = 8.3, 1.1 Hz, 1H), 7.79 (d, J = 0.8 Hz, 1H), 7.75(d, J = 0.9 Hz, 1H), 7.57 (dd, J = 7.1, 1.2 Hz, 1H), 7.51 (d, J = 1.1Hz, 1H), 7.40-7.32 (m, 3H), 7.21 (dd, J = 8.4, 1.9 Hz, 1H), 4.55-4.35(m, 2H), 4.42 (t, J = 5.2 Hz, 2H), 4.30-4.24 (m, 2H), 4.15-4.05 (m, 1H),3.98 (s, 3H), 3.85 (t, J = 5.2 Hz, 2H), 3.39 (s, 3H), 3.34 (s, 3H). LCMS(ESI) Rt = 2.57 minutes MS m/z 488 [M + H]⁺ Using3-chloro-5-(1-(2-methoxyethyl)-1H- pyrazol-4-yl)isoquinoline(Preparation 2) and purification method A. 0.014  3

¹H NMR (500 MHz, CDCl₃): δ 9.06 (d, J = 0.9 Hz, 1H), 8.05 (d, J = 8.3Hz, 1H), 7.82 (dt, J = 8.2, 1.0 Hz, 1H), 7.79 (d, J = 0.8 Hz, 1H), 7.66(d, J = 0.8 Hz, 1H), 7.53 (dd, J = 7.1, 1.2 Hz, 1H), 7.46 (d, J = 1.1Hz, 1H), 7.40-7.32 (m, 3H), 7.19 (dd, J = 8.4, 1.8 Hz, 1H), 4.55-4.20(m, 7H), 4.14-4.02 (m, 1H), 3.97 (s, 3H), 3.33 (s, 3H), 3.00- 2.90 (m,2H), 2.26-2.20 (m, 2H), 2.06- 1.97 (m, 2H), 1.49 (s, 9H). LCMS (ESI) Rt= 3.00 minutes MS m/z 613 [M + H]⁺ Using tert-butyl4-(4-(3-chloroisoquinolin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (Preparation 5) at 140° C.and purification method B. 0.125  4

¹H NMR (500 MHz, CDCl₃): δ 9.10 (d, J = 1.0 Hz, 1H), 8.08 (d, J = 8.4Hz, 1H), 7.95 (dt, J = 8.3, 1.1 Hz, 1H), 7.69 (s, 1H), 7.54 (dd, J =7.1, 1.3 Hz, 1H), 7.43 (dd, J = 8.2, 7.0 Hz, 1H), 7.39-7.32 (m, 2H),7.24- 7.15 (m, 2H), 6.99 (d, J = 1.0 Hz, 1H), 4.51- 4.35 (m, 2H),4.30-4.20 (m, 2H), 4.20- 4.10 (m, 1H), 3.97 (s, 3H), 3.48 (s, 3H), 3.34(s, 3H). LCMS (ESI) Rt = 1.73 minutes MS m/z 444 [M + H]⁺ Using3-chloro-5-(1-methyl-1H-imidazol-5- yl)isoquinoline (Preparation 4) andpurification method C. 0.112  5

¹H NMR (500 MHz, CDCl₃): δ 9.10 (d, J = 0.9 Hz, 1H), 8.07 (d, J = 8.3Hz, 1H), 7.94 (ddd, J = 6.9, 2.6, 0.9 Hz, 1H), 7.48-7.38 (m, 2H), 7.36(d, J = 2.0 Hz, 2H), 7.19 (dd, J = 8.4, 1.8 Hz, 1H), 6.85 (t, J = 1.0Hz, 1H), 4.55-4.35 (m, 2H), 4.30-4.25 (m, 2H), 4.15-4.05 (m, 1H), 3.98(s, 3H), 3.35 (s, 3H), 2.30 (s, 3H), 2.14 (s, 3H). LCMS (ESI) Rt = 2.65minutes MS m/z 459 [M + H]⁺ Using 4-(3-chloroisoquinolin-5-yl)-3,5-dimethylisoxazole (Preparation 6) at 140° C. and purification method D.0.261  6

¹H NMR (500 MHz, CDCl₃): δ 9.09 (s, 1H), 8.02 (d, J = 8.5 Hz, 1H),7.92-7.82 (m, 2H), 7.80-7.72 (m, 2H), 7.66-7.51 (m, 3H), 7.44 (t, J =7.6 Hz, 1H), 7.15-7.05 (m, 2H), 4.30-4.20 (m, 1H), 4.04 (s, 3H), 3.74-3.53 (m, 4H), 2.82-2.70 (m, 4H), 2.30- 2.10 (m, 2H), 1.35-1.22 (m, 1H).LCMS (ESI) Rt = 2.08 minutes MS m/z 525 [M + H]⁺ Using3-chloro-5-(1-methyl-1H-pyrazol-4- yl)isoquinoline (Preparation 7) and4- amino-N-(1-methylpiperidin-4-yl)-3- (trifluoromethoxy)benzamide(Preparation 26) at 140° C. and purification method E. 0.293  7

¹H NMR (500 MHz, CDCl₃) δ 9.06 (d, J = 0.9 Hz, 1H), 8.00 (d, J = 8.4 Hz,1H), 7.82 (dt, J = 8.2, 1.1 Hz, 1H), 7.78 (d, J = 0.8 Hz, 1H), 7.68 (d,J = 0.8 Hz, 1H), 7.56 (dd, J = 7.0, 1.2 Hz, 1H), 7.53 (t, J = 0.9 Hz,1H), 7.41-7.32 (m, 3H), 7.19 (dd, J = 8.4, 1.8 Hz, 1H), 4.63 (septet, J= 6.7 Hz, 1H), 4.52- 4.35 (m, 2H), 4.30-4.22 (m, 2H), 4.14- 4.06 (m,1H), 3.98 (s, 3H), 3.34 (s, 3H), 1.62 (d, J = 6.7 Hz, 6H). LCMS (ESI) Rt= 2.73 minutes MS m/z 472 [M + H]⁺ Using3-chloro-5-(1-isopropyl-1H-pyrazol-4- yl)isoquinoline (Preparation 8) at140° C. and purification method A. 0.011  8

¹H NMR (500 MHz, CDCl₃): δ 9.07 (d, J = 0.9 Hz, 1H), 8.07 (d, J = 8.4Hz, 1H), 7.85 (dt, J = 8.2, 1.1 Hz, 1H), 7.46 (dd, J = 7.0, 1.3 Hz, 1H),7.42 (s, 1H), 7.38 (dd, J = 8.2, 7.0 Hz, 1H), 7.35-7.29 (m, 2H), 7.18(dd, J = 8.4, 1.8 Hz, 1H), 7.16 (d, J = 1.0 Hz, 1H), 4.52-4.35 (m, 2H),4.28-4.22 (m, 2H), 4.15-4.07 (m, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 3.33(s, 3H), 2.20 (s, 3H). LCMS (ESI) Rt = 2.62 minutes MS m/z 458 [M + H]⁺Using 3-chloro-5-(1,3-dimethyl-1H-pyrazol- 4-yl)isoquinoline(Preparation 9) at 140° C. and purification method A. 0.027  9

¹H NMR (500 MHz, CDCl₃): δ 9.10 (d, J = 0.9 Hz, 1H), 8.06 (d, J = 8.4Hz, 1H), 7.97 (dt, J = 8.3, 1.1 Hz, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.55(dd, J = 7.0, 1.2 Hz, 1H), 7.43 (dd, J = 8.2, 7.0 Hz, 1H), 7.39-7.32 (m,2H), 7.18 (dd, J = 8.4, 1.8 Hz, 1H), 6.92 (t, J = 0.9 Hz, 1H), 6.42 (d,J = 1.9 Hz, 1H), 4.54-4.35 (m, 2H), 4.3 -4.20 (m, 2H), 4.15- 4.05 (m,1H), 3.97 (s, 3H), 3.72 (s, 3H), 3.34 (s, 3H). LCMS (ESI) Rt = 2.60minutes MS m/z 444 [M + H]⁺ Using 3-chloro-5-(1-methyl-1H-pyrazol-5-yl)isoquinoline (Preparation 10) at 140° C. and purification method A.0.022 10

¹H NMR (500 MHz, CDCl₃): δ 9.05 (d, J = 0.9 Hz, 1H), 8.01 (d, J = 8.2Hz, 1H), 7.82 (dt, J = 8.2, 1.1 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H),7.63-7.61 (m, 1H), 7.53 (dd, J = 7.0, 1.2 Hz, 1H), 7.49 (t, J = 0.9 Hz,1H), 7.38- 7.32 (m, 1H), 7.22 (s, 1H), 7.00-6.93 (m, 2H), 6.89 (d, J =1.9 Hz, 1H), 4.03 (s, 3H), 3.95 (s, 3H), 3.56 (s, 3H), 2.49 (s, 3H).LCMS (ESI) Rt = 2.00 minutes MS m/z 425 [M + H]⁺ Using3-chloro-5-(1-methyl-1H-pyrazol-4- yl)isoquinoline (Preparation 7) and4-(1,2- dimethyl-1H-imidazol-5-yl)-2- methoxyaniline (Preparation 18)and purification method A. 0.006 11

¹H NMR (500 MHz, CDCl₃): δ 9.07 (d, J = 0.9 Hz, 1H), 8.01 (d, J = 8.5Hz, 1H), 7.85 (dt, J = 8.3, 1.1 Hz, 1H), 7.75 (d, J = 0.8 Hz, 1H),7.64-7.59 (m, 1H), 7.56 (dd, J = 7.1, 1.2 Hz, 1H), 7.50 (d, J = 1.0 Hz,1H), 7.45- 7.37 (m, 2H), 7.26-7.21 (m, 1H), 7.06 (s, 1H), 6.96 (s, 1H),4.03 (s, 3H), 3.55 (s, 3H), 2.47 (s, 3H). LCMS (ESI) Rt = 1.95 minutesMS m/z 429 [M + H]⁺ Using 3-chloro-5-(1-methyl-1H-pyrazol-4-yl)isoquinoline (Preparation 7) and 2-chloro-4-(1,2-dimethyl-1H-imidazol-5- yl)aniline (Preparation 23) at140° C. 0.006 12

¹H NMR (500 MHz, CDCl₃): δ 9.05 (d, J = 0.9 Hz, 1H), 8.25 (t, J = 0.9Hz, 1H), 8.05 (d, J = 8.4 Hz, 1H),7.86 (dt, J = 8.2, 1.1 Hz, 1H), 7.81(dd, J = 7.1, 1.2 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.45-7.39 (m, 2H),7.32 (d, J = 1.8 Hz, 1H), 7.26-7.21 (m, 1H), 6.59 (d, J = 2.2 Hz, 1H),4.52-4.35 (m, 2H), 4.32-4.22 (m, 2H), 4.15-4.08 (m, 1H), 4.06 (s, 3H),3.97 (s, 3H), 3.34 (s, 3H). LCMS (ESI) Rt = 2.58 minutes MS m/z 444 [M +H]⁺ Using 3-chloro-5-(1-methyl-1H-pyrazol-3- yl)isoquinoline(Preparation 11) at 140° C. and purification method A. 0.026 13

¹H NMR (500 MHz, CDCl₃): δ 9.05 (d, J = 0.9 Hz, 1H), 8.05 (d, J = 8.4Hz, 1H), 7.83 (dt, J = 8.0, 1.2 Hz, 1H), 7.58 (s, 1H), 7.45- 7.35 (m,2H), 7.35-7.30 (m, 2H), 7.21 (t, J = 0.9 Hz, 1H), 7.18 (dd, J = 8.4, 1.8Hz, 1H), 4.52-4.34 (m, 2H), 4.28-4.22 (m, 2H), 4.15-4.04 (m, 1H), 3.95(s, 3H), 3.91 (s, 3H), 3.32 (s, 3H), 2.21 (s, 3H). LCMS (ESI) Rt = 2.60minutes MS m/z 458 [M + H]⁺ Using 3-chloro-5-(1,5-dimethyl-1H-pyrazol-4-yl)isoquinoline (Preparation 12) at 140° C. and purification method A.0.012 14

¹H NMR (500 MHz, CDCl₃): δ 9.05 (d, J = 0.9 Hz, 1H), 8.03 (d, J = 8.2Hz, 1H), 7.82 (dt, J = 8.3, 1.1 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.61(d, J = 0.8 Hz, 1H), 7.56 (s, 1H), 7.53 (dd, J = 7.1, 1.2 Hz, 1H), 7.49(t, J = 0.9 Hz, 1H), 7.35 (dd, J = 8.2, 7.0 Hz, 1H), 7.23 (s, 1H), 7.09(d, J = 1.2 Hz, 1H), 7.00 (dd, J = 8.2, 1.8 Hz, 1H), 6.92 (d, J = 1.9Hz, 1H), 4.03 (s, 3H), 3.96 (s, 3H), 3.70 (s, 3H). LCMS (ESI) Rt = 1.92minutes MS m/z 411 [M + H]⁺ Using 3-chloro-5-(1-methyl-1H-pyrazol-4-yl)isoquinoline (Preparation 7) and 2-methoxy-4-(1-methyl-1H-imidazol-5- yl)aniline (Preparation 17) at 140°C. and purification method A. 0.007 15

¹H NMR (500 MHz, CDCl₃): δ 9.33 (s, 1H), 9.13 (d, J = 1.0 Hz, 1H), 8.93(s, 2H), 8.05 (d, J = 8.3 Hz, 1H), 7.99 (dt, J = 8.3, 1.1 Hz, 1H), 7.55(dd, J = 7.0, 1.3 Hz, 1H), 7.47 (dd, J = 8.2, 6.9 Hz, 1H), 7.38-7.32 (m,2H), 7.18 (dd, J = 8.4, 1.9 Hz, 1H), 7.06 (t, J = 1.1 Hz, 1H), 4.52-4.35(m, 2H), 4.31- 4.22 (m, 2H), 4.15-4.03 (m, 1H), 3.97 (s, 3H), 3.34 (s,3H). LCMS (ESI) Rt = 2.47 minutes MS m/z 442 [M + H]⁺ Using3-chloro-5-(pyrimidin-5- yl)isoquinoline (Preparation 13) at 140° C. andpurification method A. 0.098 16

¹H NMR (500 MHz, CDCl₃): δ 9.02 (d, J = 0.9 Hz, 1H), 7.83 (d, J = 8.2Hz, 1H), 7.78 (dt, J = 8.2, 1.1 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H), 7.74(d, J = 0.8 Hz, 1H), 7.59 (d, J = 0.8 Hz, 2H), 7.50 (dd, J = 7.1, 1.2Hz, 1H), 7.47 (t, J = 1.0 Hz, 1H), 7.31 (dd, J = 8.2, 7.0 Hz, 1H),7.12-7.06 (m, 2H), 7.01 (d, J = 1.9 Hz, 1H), 4.01 (s, 3H), 3.96 (s, 3H),3.95 (s, 3H). LCMS (ESI) Rt = 2.57 minutes MS m/z 411 [M + H]⁺ Using3-chloro-5-(1-methyl-1H-pyrazol-4- yl)isoquinoline (Preparation 7) and2- methoxy-4-(1-methyl-1H-pyrazol-4- yl)aniline (Preparation 19) at 140°C. and purification method F. 0.071 17

¹H NMR (500 MHz, CDCl₃): δ 9.08 (d, J = 0.9 Hz, 1H), 8.04 (d, J = 8.5Hz, 1H), 7.86 (dt, J = 8.2, 1.1 Hz, 1H), 7.75 (d, J = 0.8 Hz, 1H), 7.62(s, 1H), 7.57 (dd, J = 7.0, 1.2 Hz, 1H), 7.53 (s, 1H), 7.51 (t, J = 1.0Hz, 1H), 7.45 (d, J = 2.1 Hz, 1H), 7.42 (dd, J = 8.2, 7.0 Hz, 1H), 7.297.26 (m, 1H), 7.10 (s, 1H), 7.05 (s, 1H), 4.04 (s, 3H), 3.70 (s, 3H).LCMS (ESI) Rt = 1.94 minutes MS m/z 415 [M + H]⁺ Using3-chloro-5-(1-methyl-1H-pyrazol-4- yl)isoquinoline (Preparation 7) and2- chloro-4-(1-methyl-1H-imidazol-5-yl)aniline (Preparation 20) at 140°C. and purification method A. 0.051 18

¹H NMR (500 MHz, CDCl₃): δ 9.04 (d, J = 0.9 Hz, 1H), 8.03 (d, J = 8.2Hz, 1H), 7.81 (dt, J = 8.2, 1.1 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H), 7.61(d, J = 0.9 Hz, 1H), 7.52 (dd, J = 7.1, 1.2 Hz, 1H), 7.49 (t, J = 0.9Hz, 1H), 7.34 (dd, J = 8.2, 7.0 Hz, 1H), 7.18 (s, 1H), 6.87 (dd, J =8.2, 1.9 Hz, 1H), 6.78 (d, J = 1.9 Hz, 1H), 4.03 (s, 3H), 3.94 (s, 3H),2.44 (s, 3H), 2.31 (s, 3H). LCMS (ESI) Rt = 2.78 minutes MS m/z 426 [M +H]⁺ Using 3-chloro-5-(1-methyl-1H-pyrazol-4- yl)isoquinoline(Preparation 7) and 4-(3,5- dimethylisoxazol-4-yl)-2-methoxyaniline(Preparation 22) at 140° C. and purification method G. 0.095

Example 19(3-Methoxy-4-((5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone

To a solution of(3-methoxy-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone(Example 20, 18 mg, 0.035 mmol) in DCM/MeOH (4/2 mL) was added aceticacid (2.5 uL, 0.044 mmol) and aqueous formaldehyde solution (38% w/w,6.0 uL, 0.073 mmol) followed by sodium triacetoxyborohydride (11.2 mg,0.053 mmol). The reaction mixture was stirred at room temperature for 1hour. Solvents were removed and the residue was purified by SCX-2column, eluting with 2M NH₃/MeOH to afford the title compound as yellowoil (17 mg, 92%).

¹H NMR (500 MHz, CDCl₃): δ 9.05 (d, J=0.9 Hz, 1H), 8.01 (d, J=8.3 Hz,1H), 7.82 (dt, J=8.3, 1.1 Hz, 1H), 7.78 (d, J=0.8 Hz, 1H), 7.69 (d,J=0.8 Hz, 1H), 7.54 (dd, J=7.1, 1.2 Hz, 1H), 7.49 (t, J=1.0 Hz, 1H),7.40-7.32 (m, 3H), 7.20 (dd, J=8.4, 1.9 Hz, 1H), 4.47-4.35 (m, 2H),4.30-4.20 (m, 2H), 4.17-4.03 (m, 1H), 3.97 (s, 3H), 3.33 (s, 3H),3.07-3.00 (m, 2H), 2.37 (s, 3H), 2.34-2.09 (m, 7H).

LCMS (ESI) Rt=1.97 minutes MS m/z 527 [M+H]⁺

MPS1 IC50 (μM): 0.031

Example 20(3-Methoxy-4-((5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)isoquinolin-3-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone

To a solution of tert-butyl4-(4-(3-((2-methoxy-4-(3-methoxyazetidine-1-carbonyl)phenyl)-amino)isoquinolin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate(Example 3, 23 mg, 0.038 mmol) in DCM (8 mL) at 0° C. was added TFA (0.5mL). The reaction was stirred at room temperature for 16 hours. Thesolvents were removed in vacuo and the residue was purified by SCX-2column eluting with 2M NH₃/MeOH to afford the title compound as yellowoil (19 mg, 98%).

¹H NMR (500 MHz, CDCl₃): δ 9.05 (d, J=0.9 Hz, 1H), 8.00 (d, J=8.3 Hz,1H), 7.81 (d, J=8.1 Hz, 1H), 7.77 (s, 1H), 7.69 (s, 1H), 7.54 (dd,J=7.1, 1.3 Hz, 1H), 7.50 (s, 1H), 7.40-7.30 (m, 3H), 7.20 (dd, J=8.3,1.9 Hz, 1H), 4.55-4.35 (m, 2H), 4.35-4.30 (m, 1H), 4.29-4.20 (m, 2H),4.15-4.05 (m, 1H), 3.96 (s, 3H), 3.33 (s, 3H), 3.32-3.27 (m, 2H),2.87-2.78 (m, 2H), 2.30-2.22 (m, 2H), 2.04-1.92 (m, 2H).

LCMS (ESI) Rt=1.97 minutes MS m/z 513 [M+H]⁺

MPS1 IC50 (μM): 0.020

Example 21(3-Methoxy-4-((5-(pyridin-3-yl)isoquinolin-3-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone

Method 2

A suspension of 3-chloro-5-(pyridin-3-yl)isoquinoline (Preparation 14,33 mg, 0.14 mmol),(4-amino-3-methoxyphenyl)(3-methoxyazetidin-1-yl)methanone (Preparation28, 32.5 mg, 0.14 mmol), xantphos (55.5 mg, 0.10 mmol), Pd(OAc)₂ (18.5mg, 0.08 mmol) and Cs₂CO₃ (366 mg, 1.12 mmol) in toluene/DMF (3/1 mL)was stirred at 120° C. under microwave irradiation for 2 hours. Thereaction mixture was filtered, diluted with NaCl solution and extractedwith EtOAc. The organic layer was purified by SCX-2 column eluting with2M NH₃/MeOH and concentrated in vacuo. The residue was purified byBiotage silica gel column chromatography eluting with 0-4% MeOH/EtOAc toafford the title compound as yellow oil (13 mg, 22%).

¹H NMR (500 MHz, CDCl₃): δ 9.12 (d, J=0.9 Hz, 1H), 8.79 (dd, J=2.4, 0.9Hz, 1H), 8.73 (dd, J=4.9, 1.6 Hz, 1H), 8.02 (d, J=8.3 Hz, 1H), 7.95 (dt,J=8.2, 1.1 Hz, 1H), 7.84 (ddd, J=7.7, 2.2, 1.6 Hz, 1H), 7.55 (dd, J=7.1,1.2 Hz, 1H), 7.51-7.42 (m, 2H), 7.33 (d, J=2.2 Hz, 2H), 7.20-7.14 (m,2H), 4.53-4.35 (m, 2H), 4.31-4.24 (m, 2H), 4.16-4.02 (m, 1H), 3.96 (s,3H), 3.35 (s, 3H).

LCMS (ESI) Rt=2.49 minutes MS m/z 441 [M+H]⁺

MPS1 IC50 (μM): 0.030

The following Examples were prepared according to Method 2 (Example 21)above using 3-chloro-5-(1-methyl-1H-pyrazol-4-yl)isoquinoline(Preparation 7) and the appropriate aniline as described for 1-2 hours.The crude reaction residues were purified as above or according to oneof the following methods:

-   Method A: Biotage silica gel column chromatography eluting with 60%    EtOAc/cyclohexane.

MPS1 Example IC50 No Name/Structure Data (μM) 22

¹H NMR (500 MHz, CDCl₃): δ 9.08 (d, J = 0.9 Hz, 1H), 8.06 (d, J = 8.0Hz, 1H), 7.85 (dd, J = 4.9, 1.6 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H), 7.73(d, J = 1.1 Hz, 1H), 7.62 (s, 1H), 7.57 (dd, J = 7.1, 1.2 Hz, 1H),7.54-7.51 (m, 2H), 7.45-7.41 (m, 1H), 7.18 (s, 1H), 4.53- 4.35 (m, 2H),4.31-4.24 (m, 2H), 4.16- 4.02 (m, 1H), 4.03 (s, 3H), 3.33 (s, 3H). LCMS(ESI) Rt = 2.60 minutes 448 [M + H]⁺ Using (4-amino-3-chlorophenyl)(3-methoxyazetidin-1-yl)methanone (Preparation 27). 0.100 23

¹H NMR (500 MHz, MeOD): δ 8.97 (d, J = 0.9 Hz, 1H), 7.95 (d, J = 0.9 Hz,1H), 7.89 (d, J = 0.8 Hz, 1H), 7.87 (dt, J = 8.3, 1.1 Hz, 1H), 7.81 (d,J = 0.8 Hz, 1H), 7.74 (d, J = 0.8 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H),7.66 (d, J = 2.0 Hz, 1H), 7.59 (dd, J = 7.1, 1.2 Hz, 1H), 7.46 (dd, J =8.4, 2.1 Hz, 1H), 7.40 (t, J = 0.9 Hz, 1H), 7.38 (dd, J = 8.2, 7.1 Hz,1H), 3.97 (s, 3H), 3.93 (s, 3H). LCMS (ESI) Rt = 2.73 minutes MS m/z 415[M + H]⁺ Using 2-chloro-4-(1-methyl-1H-pyrazol- 4-yl)aniline(Preparation 21). 0.225 24

¹H NMR (500 MHz, MeOD): δ 8.97 (d, J = 1.0 Hz, 1H), 7.99 (d, J = 8.4 Hz,1H), 7.90 (d, J = 0.8 Hz, 1H), 7.83 (dt, J = 8.4, 1.1 Hz, 1H), 7.75 (d,J = 0.9 Hz, 1H), 7.57 (dd, J = 7.1, 1.2 Hz, 1H), 7.54 (t, J = 0.9 Hz,1H), 7.36 (dd, J = 8.2, 7.1 Hz, 1H), 7.28 (d, J = 1.9 Hz, 1H), 7.21 (dd,J = 8.4, 1.9 Hz, 1H), 4.62-4.50 (m, 1H), 4.38-4.30 (m, 1H), 4.340-4.22(m, 2H), 4.03-3.95 (m, 1H + 3H), 3.94 (s, 3H). LCMS (ESI) Rt = 2.57minutes MS m/z 444 [M + H]⁺ Using (4-amino-3-methoxyphenyl)(3-methoxyazetidin-1-yl)methanone (Preparation 28). 0.020 25

¹H NMR (500 MHz, MeOD): δ 9.02 (d, J = 0.9 Hz, 1H), 7.98 (d, J = 8.2 Hz,1H), 7.95 (d, J = 0.8 Hz, 1H), 7.88 (dt, J = 8.3, 1.1 Hz, 1H), 7.78 (d,J = 0.8 Hz, 1H), 7.61 (dd, J = 7.1, 1.2 Hz, 1H), 7.56 (t, J = 1.0 Hz,1H), 7.39 (dd, J = 8.2, 7.0 Hz, 1H), 7.12 (d, J = 1.8 Hz, 1H), 7.07 (dd,J = 8.3, 1.8 Hz, 1H), 4.02 (s, 3H), 3.97 (s, 3H), 3.13 (s, 6H). LCMS(ESI) Rt = 2.57 minutes MS m/z 402 [M + H]⁺ Using 4-amino-3-methoxy-N,N-dimethylbenzamide (Preparation 24) and purification method A. 0.028 26

¹H NMR (500 MHz, MeOD): δ 9.06 (s, 1H), 8.00-7.95 (m, 2H), 7.94 (dt, J =8.3, 1.1 Hz, 1H), 7.80 (d, J = 0.8 Hz, 1H), 7.66 (dd, J = 7.1, 1.2 Hz,1H), 7.64-7.61 (m, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.46 (dd, J = 8.2, 7.1Hz, 1H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 4.02 (s, 3H), 3.12 (s, 6H).LCMS (ESI) Rt = 2.58 minutes MS m/z 406 [M + H]⁺ Using4-amino-3-chloro-N,N- dimethylbenzamide (Preparation 25) andpurification method A. 0.078

Example 27 5-(Furan-2-yl)-N-(4-methoxyphenyl)isoquinolin-3-amine

Method 3

3-Chloro-5-(furan-2-yl)isoquinoline (Preparation 15, 41 mg, 0.18 mmol),4-methoxyaniline (29 mg, 0.23 mmol), caesium carbonate (204 mg, 0.63mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (30 mg,0.071 mmol), tris(dibenzylideneacetone)dipalladium(0) (16 mg, 0.018mmol) and ^(t)BuOH (3% H₂O) (1 mL) were mixed and the mixture heated at80° C. under microwave irradiation for 3 hours. The reaction mixture wasconcentrated onto silica gel in vacuo and purified by silica gel columnchromatography eluting with 0-100% EtOAc in cyclohexane to afford thetitle compound (10 mg, 18%).

¹H NMR (500 MHz, CDCl₃): δ 8.95 (s, 1H), 7.84-7.75 (m, 2H), 7.61 (s,1H), 7.57 (s, 1H), 7.58-7.25 (m, 3H), 7.17-6.90 (m, 2H), 6.77-6.60 (m,2H), 6.54 (dd, J=3.3, 1.8 Hz, 1H), 3.85 (s, 3H).

LCMS m/z 317 [M+H]⁺ HRMS (ESI) m/z calcd for C₂₀H₁₇N₂O₂[M+H]⁺ 317.1285,found 317.1282.

MPS1 IC50 (μM): 3.657

Example 28N-(4-Methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine

The title compound was prepared according to Method 3 (Example 27) using4-methoxyaniline and 3-Chloro-5-(1-methyl-1H-pyrazol-4-yl)isoquinoline(Preparation 7).

¹H NMR (500 MHz, CDCl₃): δ 8.95 (s, 1H), 7.75 (d, J=8.2 Hz, 1H), 7.68(s, 1H), 7.52 (s, 1H), 7.50-7.46 (m, 1H), 7.31-7.21 (m, 3H), 7.03-6.89(m, 2H), 6.48 (s, 1H), 3.98 (s, 3H), 3.83 (s, 3H).

LCMS m/z 331 [M+H]⁺ HRMS (ESI) m/z calcd for C₂₀H₁₉N₄O [M+H]⁺ 331.1553.found 331.1546

MPS1 IC50 (μM): 0.666

Example 29N-(2-Methoxy-4-((1-methylpiperidin-4-yl)oxy)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine

The title compound was prepared according to Method 3 (Example 27) using3-Chloro-5-(1-methyl-1H-pyrazol-4-yl)isoquinoline (Preparation 7) and2-methoxy-4-(1-methylpiperidin-4-yloxy)aniline at 100° C. for 3 hours.The reaction mixture was concentrated onto silica gel in vacuo andpurified by silica gel column chromatography eluting with 0-100% EtOAcin cyclohexane followed by 0-10% MeOH in CH₂Cl₂ and finally eluting with10% 1M NH₃/MeOH in DCM to afford the title compound (5 mg, 5%).

¹H NMR (500 MHz, MeOD): δ 8.86 (s, 1H), 7.77 (m, 2H), 7.65 (s, 1H), 7.49(dt, J=7.6, 3.8 Hz, 1H), 7.41 (t, J=7.8 Hz, 1H), 7.26 (dd, J=8.1, 7.1Hz, 1H), 7.17 (s, 1H), 6.66 (d, J=2.6 Hz, 1H), 6.56 (dd, J=8.7, 2.6 Hz,1H), 4.40 (br s, 1H), 3.95 (s, 3H), 3.82 (s, 3H), 2.77 (br s, 2H), 2.43(br s, 2H), 2.35 (s, 3H), 2.04 (br s, 2H), 1.83 (br s, 2H).

LCMS m/z 444 [M+H]⁺ HRMS (ESI) m/z calcd for C₂₆H₃₀N₅O₂ [M+H]⁺ 444.2394,found 444.2388.

MPS1 IC50 (μM): 0.017

Example 30N-(2,4-Dimethoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)isoquinolin-3-amine

The title compound was prepared according to Method 3 (Example 27) using3-Chloro-5-(1-methyl-1H-pyrazol-4-yl)isoquinoline (Preparation 7) and2,4-dimethoxyaniline at 80° C. for 1.5 hours followed by 100° C. for 1.5hours. The reaction mixture was concentrated onto silica gel in vacuoand purified by silica gel column chromatography eluting with 0-100%EtOAc in cyclohexane to afford the title compound (22 mg, 27%).

¹H NMR (50 MHz, CDCl₃): δ 8.96 (s, 1H), 7.78-7.69 (m, 2H), 7.61 (d,J=8.6 Hz, 1H), 7.54 (s, 1H), 7.47 (dd, J=7.0, 1.0 Hz, 1H), 7.33-7.23 (m,2H), 6.73 (s, 1H), 6.58-6.49 (m, 2H), 3.99 (s, 3H), 3.85 (s, 3H), 3.83(s, 3H).

LCMS m/z 61 [M+H]⁺ HRMS (ESI) m/z calcd for C₂₁H₂₁N₄O₂ [M+H]⁺ 361.1659,found 361.1661.

MPS1 IC5 (μM): 0.074

Example 31(3-methoxy-4-((8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone

A solution of (4-amino-3-methoxyphenyl)(3-methoxyazetidin-1-yl)methanone(Preparation 28, 56 mg, 0.237 mmol), TFA (46 μL, 0.601 mmol) and8-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine(Preparation 35, 35 mg, 0.121 mmol) in 2,2,2-trifluoroethanol (0.6 mL)was heated to reflux for 5 hours and then to 80° C. for 18 hours. Thereaction was diluted with EtOAc, quenched with aqueous saturated NaHCO₃and the aqueous layer extracted with EtOAc. The combined organic layerswere washed with water, brine, dried, concentrated in vacuo and purifiedby silica gel column chromatography eluting with 0 to 100% EtOAc incyclohexane followed by a second chromatography eluting with 0 to 10%MeOH in EtOAc to afford the title compound (11 mg, 20%). ¹H ¹HNMR (500MHz, DMSO-d₆): δ 9.43 (s, 1H), 9.17 (s, 1H), 8.64 (s, 1H), 8.40 (d,J=5.2 Hz, 1H), 8.28 (s, 1H), 8.05 (d, J=8.1 Hz, 1H), 7.62 (d, J=5.2 Hz,1H), 7.42-7.28 (m, 2H), 4.56 (s, 1H), 4.33-4.20 (m, 3H), 3.89-3.87 (m,7H), 3.25 (s, 3H).

HRMS (ESI) MS m/z calcd for C₂₃H₂₄N₇O₃ [M+H]⁺ 446.1935, found 446.1925.

MPS1 IC50 (μM): —no data

Example 32N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine

Method 4

A solution of 2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline (Preparation19, 42 mg, 0.207 mmol) TFA (45 μL, 0.588 mmol) and8-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine(Preparation 35, 31 mg, 0.107 mmol) in 2,2,2-trifluoroethanol (0.6 mL)was heated to 130° C. under microwave irradiation for 1 hour 30 minutes.The reaction was diluted with EtOAc and quenched with aqueous saturatedNaHCO₃. The aqueous layer was extracted with EtOAc and the combinedorganic layers were washed with water, brine, dried, concentrated invacuo and purified by silica gel column chromatography eluting with 0 to10% MeOH in EtOAc to give the title compound (21 mg, 48%).

¹H NMR (500 MHz, DMSO-d₆): δ 9.35 (s, 1H), 9.08 (s, 1H), 8.53 (s, 1H),8.33 (d, J=5.3 Hz, 1H), 8.25-8.19 (m, 2H), 7.96 (d, J=0.9 Hz, 1H), 7.72(d, J=8.1 Hz, 1H), 7.56 (d, J=5.3 Hz, 1H), 7.36 (d, J=1.9 Hz, 1H), 7.28(dd, J=8.0, 1.9 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 3.74 (s, 3H).

HRMS (ESI) MS m/z calcd for C₂₂H₂₂N₈O [M+H]⁺ 413.1833, found 413.1823.

MPS1 IC50 (μM): 0.008

The following Examples were prepared according to Method 4 (Example 32)above using the appropriate pyridopyrimidine and the appropriate anilineas described. The crude reaction residues were purified as above oraccording to one of the following methods:

-   Method A: Biotage silica gel column chromatography eluting with    0-40% EtOAc in DCM followed by 0-60% EtOAc in cyclohexane.-   Method B: Biotage silica gel column chromatography eluting with    0-60% or 0-70% EtOAc in cyclohexane.-   Method C: Biotage silica gel column chromatography eluting with    0-100% EtOAc in cyclohexane.-   Method D: Biotage silica gel column chromatography eluting with    0-70% EtOAc in cyclohexane followed by a second chromatography    eluting with 0-2% MeOH in DCM followed by preparative HPLC eluting    with 10% to 90% MeOH in H₂O (0.1% formic acid).-   Method E: Biotage silica gel column chromatography eluting with 0-5%    MeOH in DCM.

MPS1 Example IC50 No Name/Structure Data (μM) 33

¹H NMR (500 MHz, DMSO-d₆): δ 9.69 (s, 1H), 9.40 (s, 1H), 8.39-8.32 (m,2H), 8.29 (s, 1H), 8.16 (s, 1H), 8.01 (d, J = 0.8 Hz, 1H), 7.90 (d, J =1.9 Hz, 1H), 7.73-7.64 (m, 2H), 7.59 (d, J = 5.3 Hz, 1H), 3.89 (s, 3H),3.66 (s, 3H). HRMS (ESI) MS m/z calcd for C₂₁H₁₈ClN₈ [M + H]⁺ 417.1337,found 417.1327. Using 2-chloro-4-(1-methyl-1H-pyrazol- 4-yl)aniline(Preparation 21) for 2 hours. — 34

¹H NMR (500 MHz, DMSO-d₆): δ 9.48 (s, 1H), 8.65 (s, 1H), 8.57 (d, J =5.2 Hz, 1H), 8.26-8.16 (m, 4H), 7.92 (s, 1H), 7.82 (d, J = 5.2 Hz, 1H),7.57-7.44 (m, 3H), 7.27 (d, J = 1.9 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H),3.93 (s, 3H), 3.89 (s, 3H). HRMS (ESI) MS m/z calcd for C24H21N6O [M +H]⁺ 409.1771, found 409.1763. Using 2-(methylsulfonyl)-8-phenylpyrido[3,4-d]pyrimidine (Preparation 36) and method A. 0.014 35

¹H NMR (500 MHz, DMSO-d₆): δ 9.40 (s, 1H), 8.54 (s, 1H), 8.41 (d, J =8.3 Hz, 1H), 8.28 (d, J = 5.3 Hz, 1H), 8.17 (d, J = 0.9 Hz, 1H), 7.90(d, J = 0.8 Hz, 1H), 7.56 (d, J = 5.3 Hz, 1H), 7.30 (d, J = 1.8 Hz, 1H),7.25 (dd, J = 8.2, 1.8 Hz, 1H), 3.96 (s, 3H), 3.88 (s, 3H), 3.28-3.19(m, 1H), 1.16-1.08 (m, 4H). HRMS (ESI) MS m/z calcd for C₂₁H₂₁N₆O [M +H]⁺ 373.1771, found 373.1773. Using 8-cyclopropyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 38) andpurification method B. 0.096 36

¹H NMR (500 MHz, CDCl₃): δ 9.16 (s, 1H), 8.67 (s, 1H), 8.60 (s, 1H),8.55 (s, 1H), 8.46 (d, J = 5.0 Hz, 1H), 7.90 (br s, 1H), 7.67 (s, 1H),7.52 (s, 1H), 7.38 (d, J = 5.0 Hz, 1H), 6.94 (s, 1H), 4.01 (s, 3H), 3.98(s, 3H), 3.96 (s, 3H), 2.45 (s, 3H). HRMS (ESI) MS m/z calcd forC₂₃H₂₂N₈O [M + H]⁺ 427.1989, found 427.1980; LCMS (ESI) Rt = 2.65minutes 427 [M + H]⁺ Using 2-methoxy-5-methyl-4-(1-methyl-1H-pyrazol-4-yl)aniline (Preparation 40) at 130° C. for 4.5 hours andpurification method E. 0.100 37

¹H NMR (500 MHz, DMSO-d₆): δ 9.12 (s, 1H), 8.37 (s, 1H), 8.14 (s, 1H),7.88 (d, J = 0.9 Hz, 1H), 7.87-7.79 (m, 2H), 7.24 (d, J = 1.9 Hz, 1H),7.17 (dd, J = 8.2, 1.9 Hz, 1H), 6.86 (d, J = 5.4 Hz, 1H), 3.89 (s, 3H),3.87 (s, 3H), 3.84- 3.76 (m, 4H), 1.91-1.81 (m, 4H). HRMS (ESI) MS m/zcalcd for C22H24N7O [M + H]⁺ 402.2037, found 402.2040. Using2-(methylsulfonyl)-8-(pyrrolidin-1- yl)pyrido[3,4-d]pyrimidine(Preparation 41) at 180° C. with an extra aliquot of TFA (50 uL) for afurther 2 hours and purification method C. 0.008 38

¹H NMR (500 MHz, DMSO-d₆): δ 9.13 (s, 1H), 8.51 (s, 1H), 8.16 (s, 1H),7.89 (d, J = 0.9 Hz, 1H), 7.84 (d, J = 5.3 Hz, 1H), 7.68 (d, J = 8.1 Hz,1H), 7.25 (d, J = 1.9 Hz, 1H), 7.17 (dd, J = 8.1, 1.9 Hz, 1H), 6.91 (d,J = 5.3 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.78 (q, J = 6.9 Hz, 4H),1.02 (t, J = 6.9 Hz, 6H). HRMS (ESI) MS m/z calcd for C22H26N7O [M + H]⁺404.2193, found 404.2191. Using N,N-diethyl-2-(methyl-sulfonyl)pyrido[3,4-d]pyrimidin-8- amine (Preparation 42) at 170° C. for4 hours followed by method D. 0.069 39

¹H NMR (500 MHz, DMSO-d₆): δ 9.16 (s, 1H), 8.48 (s, 1H), 8.16 (s, 1H),8.11 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 0.9 Hz, 1H), 7.78 (d, J = 5.7 Hz,1H), 7.27 (d, J = 1.9 Hz, 1H), 7.19 (dd, J = 8.2, 1.9 Hz, 1H), 6.85 (d,J = 5.7 Hz, 1H), 6.58 (d, J = 7.4 Hz, 1H), 4.39 (h, J = 6.8 Hz, 1H),3.92 (s, 3H), 3.87 (s, 3H), 2.09-1.97 (m, 1H), 1.80-1.68 (m, 2H),1.68-1.49 (m, 4H). HRMS (ESI) MS m/z calcd for C23H26N7O [M + H]⁺416.2193, found 416.2182. Using N-cyclopentyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin- 8-amine (Preparation 43) at 170°C. for 4 hours followed by method B. 0.007

Example 40N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine

A solution ofN-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)formamide(Preparation 55, 37 mg, 0.151 mmol) in THF (1 mL) was treated withsodium hydride (10 mg, 0.250 mmol) at 0° C. After stirring for 20minutes at room temperature, the mixture was cooled to 0° C. and8-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine(Preparation 35, 50 mg, 0.173 mmol) was added. The reaction was allowedto reach room temperature and stirred for 18 hours. Aqueous NaOH (2M,0.5 mL) and MeOH (0.5 mL) were added and the resulting mixture stirredat room temperature for 1 hour. The volatiles were removed under reducedpressure and the residue was partitioned between EtOAc and water. Theaqueous layer was extracted with EtOAc and the combined organic layerswere washed with water, brine, dried and evaporated. The residue waspurified by silica gel column chromatography eluting with 0 to 10% MeOHin EtOAc to give the title compound (9 mg, 14%).

¹H NMR (500 MHz, DMSO-d₆): δ 9.39 (s, 1H), 9.12 (s, 1H), 8.63 (s, 1H),8.36 (d, J=5.3 Hz, 1H), 8.25 (s, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.59 (d,J=5.2 Hz, 1H), 7.17 (s, 1H), 7.13 (d, J=8.4 Hz, 1H), 6.97 (s, 1H), 3.86(s, 3H), 3.82 (s, 3H), 3.62 (s, 3H), 2.38 (s, 3H).

HRMS (ESI) MS m/z calcd for C₂₃H₂₃N₈O [M+H]⁺ 427.1989, found 427.1991.

MPS1 IC50 (μM): 0.004

Example 41N³-cyclohexyl-N2-(2-methoxy-4-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine

The title compound was prepared according to Example 40 above usingN-(2-methoxy-4-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)phenyl)formamide(Preparation 61) andN-cyclohexyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-amine(Preparation 44). The residue was purified by silica gel columnchromatography eluting with 0 to 15% MeOH in DCM to give the titlecompound (51 mg, 48%).

¹H NMR (500 MHz, DMSO-d₆): δ 9.16 (s, 1H), 8.50 (s, 1H), 8.19 (s, 1H),8.11 (d, J=8.2 Hz, 1H), 7.90 (s, 1H), 7.77 (d, J=5.7 Hz, 1H), 7.27 (d,J=2.0 Hz, 1H), 7.19 (dd, J=8.3, 1.9 Hz, 1H), 6.85 (d, J=5.6 Hz, 1H),6.51 (d, J=8.0 Hz, 1H), 4.22 (t, J=6.7 Hz, 2H), 3.99 (br s, 1H), 3.93(s, 3H), 2.74 (t, J=6.7 Hz, 2H), 2.45 (br s, 4H), 2.34 (br s, 4H), 2.16(s, 3H), 1.99 (br s, 2H), 1.72 (br s, 2H), 1.60 (s, 1H), 1.45-1.34 (d,4H), 1.29 (br s, 1H).

HRMS (ESI) MS m/z calcd for C₃₀H₄₀N₉O [M+H]⁺ 542.3350, found 542.3320.

MPS1 IC50 (μM): 0.003

Example 42N8-cyclohexyl-N2-(4-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)pyrido[3,4-d]pyrimidine-2,8-diamine

The title compound was prepared according to Example 40 usingN-(4-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide(Preparation 64) andN-cyclohexyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-amine(Preparation 44). The residue was purified by silica gel columnchromatography eluting with 0 to 10% MeOH in DCM to give the titlecompound (26 mg, 25%).

¹H NMR (500 MHz, DMSO-d₆): δ 9.17 (s, 1H), 8.51 (s, 1H), 8.21 (d, J=0.9Hz, 1H), 8.12 (d, J=8.2 Hz, 1H), 7.91 (d, J=0.8 Hz, 1H), 7.78 (d, J=5.7Hz, 1H), 7.28 (d, J=1.9 Hz, 1H), 7.21 (dd, J=8.2, 1.9 Hz, 1H), 6.86 (d,J=5.7 Hz, 1H), 6.52 (d, J=8.1 Hz, 1H), 4.22 (t, J=6.6 Hz, 2H), 4.05-3.96(m, 1H), 3.94 (s, 3H), 2.70 (t, J=6.5 Hz, 2H), 2.20 (s, 6H), 2.07-1.96(m, 2H), 1.78-1.69 (m, 2H), 1.62 (br d, J=12.3 Hz, 1H), 1.48-1.34 (m,4H), 1.34-1.23 (m, 1H).

HRMS (ESI) MS m/z calcd for C₂₇H₃₅N₈O [M+H]⁺ 487.2928, found 487.2921

MPS1 IC50 (μM): 0.003

Example 432-(4-(4-((8-(cyclohexylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)-1H-pyrazol-1-yl)ethanol

A solution ofN-(4-(1-(2-(tert-butyldiphenylsilyloxy)ethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide(Preparation 67, 124 mg, 0.248 mmol) in THF (1.5 mL) was treated withsodium hydride (14 mg, 0.350 mmol) at 0° C. After stirring for 25minutes at room temperature, the mixture was cooled to 0° C. andN-cyclohexyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-amine(Preparation 44, 79 mg, 0.258 mmol) was added. The reaction was allowedto reach room temperature and stirred for 18 hours. Aqueous NaOH (2M, 1mL) and MeOH (1 mL) were added and the resulting mixture stirred for 1hour. The volatiles were removed under reduced pressure and the residuewas partitioned between EtOAc and water. The aqueous layer was extractedwith EtOAc and the combined organic layers were washed with water,brine, dried and evaporated. The residue was purified by silica gelcolumn chromatography eluting with 0 to 30% EtOAc in cyclohexane to givethe silyl ether (53 mg, 31%).

A solution of silyl ether (30 mg, 0.043 mmol) in THF (0.4 mL) wastreated with TBAF (1M in THF, 100 μl, 0.100 mmol) at room temperaturefor 2 hours. The volatiles were removed under reduced pressure and theresidue was adsorbed on silica. The residue was purified by silica gelcolumn chromatography eluting with 0 to 100% EtOAc in cyclohexane togive the title compound (12 mg, 60%).

¹H NMR (500 MHz, DMSO-d₆): δ 9.17 (s, 1H), 8.50 (s, 1H), 8.18 (s, 1H),8.12 (d, J=8.2 Hz, 1H), 7.92 (s, 1H), 7.78 (d, J=5.6 Hz, 1H), 7.29 (d,J=1.9 Hz, 1H), 7.22 (dd, J=8.2, 1.9 Hz, 1H), 6.86 (d, J=5.7 Hz, 1H),6.52 (d, J=8.2 Hz, 1H), 4.95 (t, J=5.2 Hz, 1H), 4.17 (t, J=5.7 Hz, 2H),4.07-3.96 (m, 1H), 3.83-3.76 (m, 2H), 2.05-1.96 (m, 2H), 1.79-1.69 (m,2H), 1.62 (br d, J=12.6 Hz, 1H), 1.45-1.33 (m, 4H), 1.30-1.22 (m, 1H).

HRMS (ESI) MS m/z calcd for C₂₅H₃₀N₇O₂ [M+H]⁺ 460.2455, found 460.2454.

MPS1 IC50 (μM): 0.014

Example 442-(4-(3-methoxy-4-((8-((tetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)ethanol

The title compound was prepared according to Example 43 usingN-(4-(1-(2-(tert-butyldiphenylsilyloxy)ethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide(Preparation 67) and2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidin-8-amine(Preparation 45). The intermediate silyl ether was purified using silicagel column chromatography eluting with 0 to 55% EtOAc in cyclohexane andthe title compound was purified using silica gel column chromatographyeluting with 0 to 5% MeOH in EtOAc (6 mg, 85%).

¹H NMR (500 MHz, CDCl₃): δ 9.00 (s, 1H), 8.51 (d, J=8.3 Hz, 1H), 7.98(s, 1H), 7.89 (d, J=5.7 Hz, 1H), 7.84 (s, 1H), 7.74 (s, 1H), 7.19 (dd,J=8.3, 1.8 Hz, 1H), 7.06 (d, J=1.9 Hz, 1H), 6.79 (d, J=5.7 Hz, 1H), 6.40(br s, 1H), 4.42-4.30 (m, 3H), 4.12-4.04 (m, 4H), 4.02 (s, 3H),3.73-3.62 (m, 2H), 3.05 (br s, 1H), 2.20 (br d, J=12.6 Hz, 2H),1.80-1.66 (m, 2H).

HRMS (ESI) MS m/z calcd for C₂₄H₂₈N₇O₃ [M+H]⁺ 462.2248, found 462.2239

MPS1 IC50 (μM): 0.003

Example 45N²-(2-methoxy-6-morpholinopyridin-3-yl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine

The title compound was prepared according to Example 40 usingN-(2-methoxy-6-morpholinopyridin-3-yl)formamide (Preparation 71) and2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine(Preparation 47). The residue was purified by silica gel columnchromatography eluting with 0-5% MeOH EtOAc followed by a secondchromatography eluting with 50-100% EtOAc in cyclohexane. The residuewas dissolved in EtOAc and washed with HCl (0.5 M, 10 mL), dried (MgSO₄)and concentrated in vacuo. The residue was further purified by passagethrough a SCX-2 cartridge eluting with 100% MeOH—1 M NH₃ in MeOH, toafford the title compound (10 mg, 14%).

¹H NMR (500 MHz, CDCl₃): δ 8.93 (s, 1H), 8.52 (d, J=8.5 Hz, 1H), 7.85(d, J=6.0 Hz, 1H), 7.48 (br s, 1H), 6.72 (d, J=6.0 Hz, 1H), 6.53 (br s,1H), 6.22 (d, J=8.5 Hz, 1H), 4.01 (s, 3H), 3.88 (app t, J=5.0 Hz, 4H),3.46 (t, J=5.0 Hz, 4H), 3.44 (d, J=6.0 Hz, 2H), 1.10 (s, 9H).

HRMS (ESI) MS m/z calcd for C₂₂H₂₉N₇O₂ [M+H]⁺ 424.2455, found 424.2446;LCMS (ESI) Rt=2.18 minutes MS m/z 424.07 [M+H]⁺

MPS1 IC50 (μM): 0.013

Example 46N2-(2-methoxy-6-(methylsulfonyl)pyridin-3-yl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine

The title compound was prepared according to Example 40 usingN-(2-methoxy-6-(methylsulfonyl)pyridin-3-yl)formamide (Preparation 73)and 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine(Preparation 47). The residue was purified by silica gel columnchromatography eluting with 50-100% EtOAc in cyclohexane. The residuewas dissolved in EtOAc and washed with HCl (0.5 M, 10 mL), dried (MgSO₄)and concentrated in vacuo. The residue was triturated with DCM and driedunder vacuum to give the title compound (3 mg, 6%).

¹H NMR (500 MHz, CDCl₃): δ 9.09 (s, 1H), 9.01 (d, J=8.0 Hz, 1H), 8.14(br s, 1H), 7.99 (d, J=5.5 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 6.81 (d,J=5.5 Hz, 1H), 6.48 (br t, J=6.5 Hz, 1H), 4.20 (s, 3H), 3.49 (d, J=6.5Hz, 2H), 3.23 (s, 3H), 1.12 (s, 9H).

HRMS (ESI) MS m/z calcd for C₁₉H₂₄N₆O₃S [M+H]⁺ 417.1703, found 417.1699;LCMS (ESI) Rt=2.02 minutes MS m/z 416.99 [M+H]⁺

MPS1 IC50 (μM): 0.017

Example 47N2-(2-methoxy-4-(1-methyl-1H-imidazol-5-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine

The title compound was prepared according to Example 40 usingN-(2-methoxy-4-(1-methyl-1H-imidazol-5-yl)phenyl)formamide (Preparation74) and 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine(Preparation 47). The residue was purified by silica gel columnchromatography eluting with 0-20% MeOH in EtOAc followed by a secondchromatography eluting with 0-10% MeOH in EtOAc to give the titlecompound (7.5 mg, 38%).

¹H NMR (500 MHz, CDCl₃): δ 9.01 (s, 1H), 8.68 (d, J=8 Hz, 1H), 8.06 (s,1H), 7.91 (d, J=6.0 Hz, 1H), 7.68 (s, 1H), 7.15 (s, 1H), 7.03 (dd,J=8.0, 1.5 Hz, 1H), 6.97 (d, J=1.5 Hz, 1H), 6.76 (d, J=6.0 Hz, 1H), 6.63(br t, J=6.5 Hz, 1H), 4.00 (s, 3H), 3.72 (s, 3H), 3.49 (d, J=6.5 Hz,2H), 1.12 (s, 9H).

HRMS (ESI) MS m/z calcd for C₂₃H₂₇N₇O [M+H]⁺ 418.2360, found 418.2341;LCMS (ESI) Rt=1.45 minutes MS m/z 418.12 [M+H]⁺

MPS1 IC50 (μM): 0.002

Example 48N2-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine

The title compound was prepared according to Example 40 usingN-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide(Preparation 76) and2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine(Preparation 47). The residue was purified by silica gel columnchromatography eluting with 50-100% EtOAc in cyclohexane to give thetitle compound (4 mg, 21%).

¹H NMR (500 MHz, CDCl₃): δ 8.98 (s, 1H), 8.60 (d, J=8.5 Hz, 1H), 7.97(br s, 1H), 7.89 (d, J=6.0 Hz, 1H), 7.45 (s, 1H), 7.03 (dd, J=8.5, 2.0Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 6.74 (d, J=6.0 Hz, 1H), 6.63 (br t,J=6.5 Hz, 1H), 3.99 (s, 3H), 3.91 (s, 3H), 3.47 (d, J=6.5 Hz, 2H), 2.43(s, 3H), 1.12 (s, 9H).

HRMS (ESI) MS m/z calcd for C₂₄H₂₉N₇O [M+H]⁺ 432.2506, found 432.2502;LCMS (ESI) Rt=2.37 minutes MS m/z 432.09 [M+H]⁺

MPS1 IC50 (μM): 0.005

Example 49N2-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine

The title compound was prepared according to Example 40 usingN-(4-(1,5-dimethy-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide(Preparation 77) and2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine(Preparation 47). The residue was purified by silica gel columnchromatography eluting with 50-100% EtOAc in cyclohexane followed by asecond chromatography eluting with, 50-90% EtOAc in cyclohexane. Theresidue was passed through a SCX-2 cartridge eluting with 100% MeOH-1MNH₃ in MeOH to give the title compound (5 mg, 8%).

¹H NMR (500 MHz, CDCl₃): δ 9.02 (s, 1H), 8.51 (br s, 1H), 8.05 (m, 1H),7.84 (m, 1H), 7.58 (s, 1H), 6.99 (dd, J=8.0, 1.5 Hz, 1H), 6.96 (d, J=1.5Hz, 1H), 6.80 (br s, 1H), 3.99 (s, 3H), 3.88 (s, 3H), 3.64 (br s, 2H),2.42 (s, 3H), 1.14 (s, 9H).

HRMS (ESI) MS m/z calcd for C₂₄H₂₉N₇O [M+H]⁺ 432.2506, found 432.2504;LCMS (ESI) Rt=2.33 minutes MS m/z 432.10 [M+H]⁺

MPS1 IC50 (μM): 0.005

Example 50N2-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine

The title compound was prepared according to Example 40 usingN-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)formamide(Preparation 55) and2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine(Preparation 47). The residue was purified by silica gel columnchromatography eluting with 0-10% MeOH in EtOAc. The residue waspurified by passage through a SCX-2 cartridge eluting with 100% MeOH-1MNH₃ in MeOH. The residue was diluted with DCM (30 mL) and washed with0.1M HCl (30 mL), dried (MgSO₄) and concentrated in vacuo. The residuewas further purified by SCX-2 cartridge eluting with 100% MeOH-1M NH₃ inMeOH followed by silica gel column chromatography eluting with 0-7% MeOHin EtOAc to give the title compound (5.5 mg, 21%).

¹H NMR (500 MHz, CDCl₃): δ 9.04 (s, 1H), 8.76 (d, J=8.0 Hz, 1H), 8.12(s, 1H), 7.94 (d, J=6.0 Hz, 1H), 7.21 (s, 1H), 6.99 (dd, J=8.0, 2.0 Hz,1H), 6.91 (d, J=2.0 Hz, 1H), 6.79 (d, J=6.0 Hz, 1H), 6.58 (br s, 1H),4.02 (s, 3H), 3.67 (s, 3H), 3.50 (d, J=6.0 Hz, 2H), 2.82 (s, 3H), 1.12(s, 9H).

HRMS (ESI) MS m/z calcd for C₂₄H₂₉N₇O [M+H]⁺ 432.2506, found 432.2504;LCMS (ESI) Rt=1.49 minutes MS m/z 432.37 [M+H]⁺

MPS1 IC50 (μM): 0.007

Example 51N²-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine

To a cooled (0° C.) suspension ofN-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide (Preparation56, 8.5 mg, 0.037 mmol) in THF (1 mL) was added NaH (60% dispersion inoil, 2.4 mg, 0.059 mmol). The reaction mixture was stirred at roomtemperature for 10 minutes. The reaction mixture was cooled to 0° C. and6-methyl-2-(methysulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine(Preparation 54, 12.5 mg, 0.040 mmol) in THF (1 mL) was added. Thereaction mixture was stirred for 5 hours, whilst slowly warming to roomtemperature. The reaction mixture was concentrated in vacuo. The residuewas partitioned between EtOAc (30 mL) and water (30 mL). The aqueouslayer was re-extracted with EtOAc and DCM (25 mL). The combined organiclayers were washed with water (25 mL) and brine (25 mL), dried (MgSO₄)and concentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with 50-100% EtOAc in cyclohexane. The residuewas purified by passage through a SCX-2 cartridge eluting with 100%MeOH-1M NH₃ in MeOH to give the title compound (5.0 mg, 32%).

¹H NMR (500 MHz, MeOD): δ 8.98 (s, 1H), 8.42 (d, J=8.5 Hz, 1H), 7.97 (s,1H), 7.83 (s, 1H), 7.23 (d, J=2.0 Hz, 1H), 7.15 (dd, J=8.5, 2.0 Hz, 1H),6.68 (s, 1H), 4.02 (s, 3H), 3.95 (s, 3H), 3.44 (s, 2H), 2.43 (s, 3H),1.10 (s, 9H).

HRMS (ESI) MS m/z calcd for C₂₄H₂₉N₇O [M+H]⁺ 432.2506, found 432.2505;LCMS (ESI) Rt=2.32 minutes MS m/z 432.36 [M+H]⁺

MPS1 IC50 (μM): 0.029

Example 52N2-(2-methoxy-4-morpholinophenyl)-N8-neopentyprido[3,4-d]pyrimidine-2,8-diamine

The title compound was prepared according to Example 40 usingN-(2-methoxy-4-morpholinophenyl)formamide (Preparation 80) and2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine(Preparation 47). The residue was purified by silica gel columnchromatography eluting with 50-100% EtOAc in hexane to give the titlecompound (55.5 mg, 77%).

¹H NMR (500 MHz, MeOD): δ 9.01 (s, 1H), 8.11 (d, J=9.0 Hz, 1H), 7.66 (d,J=6.0 Hz, 1H), 6.81 (d, J=6.0 Hz, 1H), 6.73 (d, J=2.5 Hz, 1H), 6.58 (dd,J=9.0, 2.5 Hz, 1H), 3.93 (s, 3H), 3.88-3.86 (m, 4H), 3.37 (s, 2H),3.17-3.15 (m, 4H), 1.06 (s, 9H).

HRMS (ESI) MS m/z calcd for C₂₃H₃₀N₆O₂ [M+H]⁺ 423.2503, found 423.2498;LCMS (ESI) Rt=2.07 minutes MS m/z 423.36 [M+H]⁺

MPS1 IC50 (μM): 0.008

Example 538-(cyclopropylmethoxy)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine

The title compound was prepared according to Example 40 usingN-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide (Preparation56) and 8-(cyclopropylmethoxy)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine(Preparation 69). The residue was purified by silica gel columnchromatography eluting with 0 to 75% EtOAc in cyclohexane to give thetitle compound (27 mg, 52%).

¹H NMR (500 MHz, DMSO): δ 9.31 (s, 1H), 8.61 (s, 1H), 8.39 (s, 1H), 8.17(d, J=0.8 Hz, 1H), 7.94-7.84 (m, 2H), 7.35 (d, J=5.6 Hz, 1H), 7.28 (d,J=1.8 Hz, 1H), 7.19 (dd, J=8.3, 1.8 Hz, 1H), 4.33 (d, J=6.9 Hz, 2H),3.94 (s, 3H), 3.88 (s, 3H), 1.45-1.33 (m, 1H), 0.68-0.59 (m, 2H),0.49-0.39 (m, 2H).

HRMS (ESI) MS m/z calcd for C₂₂H₂₃N₆O₂ [M+H]⁺ 403.1877, found 403.1871.

MPS1 IC50 (μM): 0.098

Example 54N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-2-amine

Method 5

A mixture of8-chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine(Example 94, 27 mg, 0.074 mmol) and piperidine (100 μL, 1.010 mmol) inN-methyl-2-pyrrolidinone (0.7 mL) was stirred at 120° C. for 2 hours ina closed cap vial. The reaction was quenched with saturated aqueousNaHCO₃ and extracted with EtOAc. The combined organic layers were washedwith water and brine, dried and concentrated. The residue was purifiedby silica gel column chromatography eluting with 0 to 80% EtOAc incyclohexane to give the title compound (24 mg, 77%).

¹H NMR (500 MHz, DMSO-d₆): δ 9.25 (s, 1H), 8.44 (s, 1H), 8.25 (d, J=8.2Hz, 1H), 8.18 (d, J=0.9 Hz, 1H), 7.97 (d, J=5.3 Hz, 1H), 7.91 (d, J=0.8Hz, 1H), 7.28 (d, J=1.8 Hz, 1H), 7.20 (dd, J=8.2, 1.8 Hz, 1H), 7.16 (d,J=5.3 Hz, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.77-3.69 (m, 4H), 1.76-1.57(m, 6H).

HRMS (ESI) MS/z calcd for C₂₃H₂₆N₇O [M+H]⁺ 416.2193, found 416.2190.

MPS1 IC50 (μM):—no data

The following Examples were prepared according to Method 5 (Example 54)above using8-chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine(Example 94) and the appropriate amine as described. Where the aminehydrochloride was used, triethylamine (190 uL, 0.373 mmol) was alsoadded to the reaction. The crude reaction residues were purified asabove or according to one of the following methods:

-   Method A: Silica gel column chromatography eluting with 0-5% or    0-10% MeOH in DCM.-   Method B: Silica gel column chromatography eluting with 0-5% MeOH in    EtOAc.-   Method C: Silica gel column chromatography eluting with 0-70% EtOAc    in cyclohexane followed by reverse phase preparative HPLC eluting    with 10-90% MeOH in water (0.1% formic acid).

MPS1 Example IC50 No Name/Structure Data (μM) 55N8-cyclohexyl-N2-(2-methoxy- 4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.16 (s, 1H), 8.51 (s, 1H), 8.17 (s, 1H),8.11 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 0.9 Hz, 1H), 7.78 (d, J = 5.7 Hz,1H), 7.28 (d, J = 1.9 Hz, 1H), 7.21 (dd, J = 8.2, 1.9 Hz, 1H), 6.86 (d,J = 0 5.7 Hz, 1H), 6.52 (d, J = 8.1 Hz, 1H), 3.99 (br s, 1H), 3.93 (s,3H), 3.88 (s, 3H), 2.04-1.94 (m, 2H), 1.79-1.69 (m, 2H), 1.65-1.59 (m,1H), 1.45-1.34 (m, 4H), 1.33-1.23 (m, 1H). HRMS (ESI) MS m/z calcd forC₂₄H₂₈N₇O [M + H]⁺ 430.2350, found 430.2347. Using cyclohexylamine at130° C. for 6 hours. 0.009 56 N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(3- methylpyrrolidin-1-yl)pyrido[3,4-d]pyrimidin-2- amine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.12 (s, 1H), 8.44 (s, 1H), 8.15 (d, J =0.5 Hz, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.81 (d, J = 5.4 Hz, 1H), 7.78(d, J = 8.2 Hz, 1H), 7.25 (d, J = 1.9 Hz, 1H), 7.16 (dd, J = 8.1, 1.8Hz, 1H), 6.85 (d, J = 5.4 Hz, 1H), 4.15-4.00 (m, 1H), 3.88 (s, 3H),3.89-3.83 (m, 4H), 3.71 (q, J = 10.9, 9.6 Hz, 1H), 3.37-3.30 (m, 1H),2.26- 2.15 (m, 1H), 2.05-1.94 (m, 1H), 1.54- 1.38 (m, 1H), 1.03 (d, J =6.6 Hz, 3H). HRMS (ESI) MS m/z calcd for C₂₃H₂₆N₇O [M + H]⁺ 416.2193,found 416.2201. Using 3-methylpyrrolidine hydrochloride. 0.010 578-(3,3-difluoropyrrolidin-1-yl)- N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4- d]pyrimidin-2-amine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.19 (s, 1H), 8.71 (s, 1H), 8.15 (d, J =1.0 Hz, 1H), 7.92-7.85 (m, 2H), 7.67 (d, J = 8.1 Hz, 1H), 7.26 (d, J =1.9 Hz, 1H), 7.16 (dd, J = 8.2, 1.8 Hz, 1H), 7.03 (d, J = 5.5 Hz, 1H),4.23 (t, J = 13.7 Hz, 2H), 3.95 (t, J = 7.3 Hz, 2H), 3.88 (s, 3H), 3.87(s, 3H), 2.43 (tt, J = 14.3, 7.4 Hz, 2H). ¹⁹F NMR (471 MHz, DMSO-d₆): δ−100.17 (s). HRMS (ESI) MS m/z calcd for C₂₂H₂₂F₂N₇O [M + H]⁺ 438.1848,found 438.1839. Using 3,3-difluoropyrrolidine hydrochloride for 5 hours.0.012 58 N8-(cyclopropylmethyl)-N2-(2- methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.17 (s, 1H), 8.43 (s, 1H), 8.20 (d, J =8.2 Hz, 1H), 8.15 (s, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.77 (d, J = 5.6Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.21 (dd, J = 8.3, 1.8 Hz, 1H), 6.90(t, J = 5.7 Hz, 1H), 6.85 (d, J = 5.7 Hz, 1H), 3.93 (s, 3H), 3.87 (s,3H), 3.41-3.35 (m, 2H), 1.26-1.14 (m, 1H), 0.54-0.43 (m, 2H), 0.35-0.26(m, 2H). HRMS (ESI) MS m/z calcd for C₂₂H₂₄N₇O [M + H]⁺ 402.2037, found402.2030 Using cyclopropylmethanamine at 130° C. for 7 hours. 0.006 59N8-cyclopentyl-N2-(2- methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-N8-methylpyrido[3,4-d]pyrimidine- 2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.49 (s, 1H), 8.16 (s, 1H),7.92-7.85 (m, 3H), 7.26 (d, J = 1.9 Hz, 1H), 7.17 (dd, J = 8.0, 1.9 Hz,1H), 7.02 (d, J = 5.3 Hz, 1H), 5.47-5.36 (m, 1H), 3.88 (s, 3H), 3.87 (s,3H), 3.00 (s, 3H), 1.73-1.64 (m, 2H), 1.62- 1.55 (m, 4H), 1.46-1.37 (m,2H). HRMS (ESI) MS m/z calcd for C₂₄H₂₈N₇O [M + H]⁺ 430.2350, found430.2360 Using N-methylcyclopentanamine at 130° C. for 12 hours. 0.04560 N8-isopentyl-N2-(2-methoxy-4- (1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.17 (s, 1H), 8.40 (s, 1H), 8.23 (d, J =8.3 Hz, 1H), 8.15 (d, J = 0.8 Hz, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.79(d, J = 5.6 Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.20 (dd, J = 8.2, 1.9Hz, 1H), 6.89- 6.79 (m, 2H), 3.94 (s, 3H), 3.88 (s, 3H), 3.54 (ddd, J =8.4, 7.2, 5.9 Hz, 2H), 1.74-1.64 (m, 1H), 1.58-1.50 (m, 2H), 0.95 (d, J= 6.6 Hz, 6H). HRMS (ESI) MS m/z calcd for C₂₃H₂₈N₇O [M + H]⁺ 418.2350,found 418.2355. Using 3-methylbutan-1-amine for 3 hours. 0.021 61N-(2-methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-8-morpholinopyrido[3,4- d]pyrimidin-2-amine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.27 (s, 1H), 8.59 (s, 1H), 8.20 (s, 1H),8.04 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 5.4 Hz, 1H), 7.93 (d, J = 0.9 Hz,1H), 7.28 (d, J = 1.8 Hz, 1H), 7.25- 7.20 (m, 2H), 3.91 (s, 3H), 3.88(s, 3H), 3.79-3.67 (m, 8H). HRMS (ESI) MS m/z calcd for C₂₂H₂₄N₇O₂ [M +H]⁺ 418.1986, found 418.1983. Using morpholine for 3 hours. 0.003 62N-(2-methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-8-(4-methylpiperazin-1- yl)pyrido[3,4-d]pyrimidin-2- amine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.26 (s, 1H), 8.53 (s, 1H), 8.17 (s, 1H),8.11 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 5.4 Hz, 1H), 7.91 (s, 1H), 7.28(d, J = 2.0 Hz, 1H), 7.23-7.14 (m, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 3.77(br s, 4H), 2.50 (br s, 4H), 2.26 (s, 3H). HRMS (ESI) MS m/z calcd forC₂₃H₂₇N₈O [M + H]⁺ 431.2302, found 431.2295 Using 1-methylpiperazine at130° C. for 6 hours and purified using method A. 0.009 638-(3,3-difluoroazetidin-1-yl)-N- (2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4- d]pyrimidin-2-amine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.25 (s, 1H), 8.68 (s, 1H), 8.19 (d, J =0.9 Hz, 1H), 7.92 (s, 1H), 7.90 (d, J = 5.5 Hz, 1H), 7.80 (d, J = 8.2Hz, 1H), 7.29 (d, J = 1.9 Hz, 1H), 7.22 (dd, J = 8.1, 1.9 Hz, 1H), 7.14(d, J = 5.5 Hz, 1H), 4.68-4.57 (m, 4H), 3.89 (s, 3H), 3.88 (s, 3H). ¹⁹FNMR (471 MHz, DMSO-d₆): δ −99.23 (s). HRMS (ESI) MS m/z calcd forC₂₁H₂₀F₂N₇O [M + H]⁺ 424.1692, found 424.1681. Using3,3-difluoroazetidine hydrochloride at 130° C. for 4 hours. 0.025 64N-(2-methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-8-(2-methylpyrrolidin-1- yl)pyrido[3,4-d]pyrimidin-2- amine  

1H NMR (500 MHz, DMSO-d₆): δ 9.12 (s, 1H), 8.44 (s, 1H), 8.15 (s, 1H),7.89 (d, J = 0.9 Hz, 1H), 7.83 (d, J = 5.4 Hz, 1H), 7.75 (d, J = 8.1 Hz,1H), 7.24 (d, J = 1.9 Hz, 1H), 7.17 (dd, J = 8.2, 1.8 Hz, 1H), 6.87 (d,J = 5.4 Hz, 1H), 4.90-4.76 (m, 1H), 4.03-3.93 (m, 1H), 3.87 (s, 6H),3.80-3.70 (m, 1H), 2.05- 1.97 (m, 1H), 1.96-1.87 (m, 1H), 1.83- 1.72 (m,1H), 1.63-1.52 (m, 1H), 1.03 (d, J = 6.1 Hz, 3H). HRMS (ESI) MS m/zcalcd for C₂₃H₂₆N₇O [M + H]⁺ 416.2193, found 416.2180. Using2-methylpyrrolidine at 130° C. for 5 hours. 0.006 65N8-isobutyl-N2-(2-methoxy-4- (1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.16 (s, 1H), 8.43 (s, 1H), 8.19 (d, J =8.3 Hz, 1H), 8.15 (d, J = 0.8 Hz, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.77(d, J = 5.7 Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.18 (dd, J = 8.2, 1.9Hz, 1H), 6.85 (dd, J = 9.3, 5.8 Hz, 2H), 3.93 (s, 3H), 3.87 (s, 3H),3.39-3.28 (m, 2H), 1.99 (dp, J = 13.5, 6.7 Hz, 1H), 0.95 (d, J = 6.7 Hz,6H). HRMS (ESI) MS m/z calc for C₂₂H₂₆N₇O [M + H]⁺ 404.2193, found404.2177. Using 2-methylpropan-1-amine at 130° C. for 5 hours. 0.008 66N-(2-methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-8-(6-azaspiro[3.4]octan-6- yl)pyrido[3,4-d]pyrimidin-2- amine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.10 (s, 1H), 8.47 (s, 1H), 8.14 (s, 1H),7.87 (s, 1H), 7.78 (d, J = 5.4 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.27(d, J = 1.8 Hz, 1H), 7.17 (dd, J = 8.1, 1.8 Hz, 1H), 6.83 (d, J = 5.4Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.82 (s, 2H), 3.74- 3.68 (m, 2H),1.92-1.81 (m, 8H). HRMS (ESI) MS m/z calcd for C₂₅H₂₈N₇O [M + H]⁺442.2350, found 442.2326 Using 6-azaspiro[3,4]octane at 130° C. for 4hours. 0.008 67 N-(2-methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-8-(3-methoxyazetidin-1- yl)pyrido[3,4-d]pyrimidin-2- amine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.17 (s, 1H), 8.51 (s, 1H), 8.17 (s, 1H),7.90 (d, J = 0.9 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 5.5 Hz,1H), 7.27 (d, J = 1.8 Hz, 1H), 7.19 (dd, J = 8.2, 1.8 Hz, 1H), 6.96 (d,J = 5.5 Hz, 1H), 4.48-4.39 (m, 2H), 4.32-4.22 (m, 1H), 4.12-4.02 (m,2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.22 (s, 3H). HRMS (ESI) MS m/z calcdfor C₂₂H₂₄N₇O₂ [M + H]⁺ 418.1986, found 418.1966. Using3-methoxyazetidine hydrochloride at 130° C. for 5 hours and purificationmethod B. 0.010 68 N8-cyclohexyl-N2-(4-(1-(2- (dimethylamino)ethyl)-1H-pyrazol-4-yl)-2- methoxyphenyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.17 (s, 1H), 8.56 (s, 1H), 8.21-8.07 (m,2H), 7.88 (d, J = 0.8 Hz, 1H), 7.76 (d, J = 5.6 Hz, 1H), 7.28 (d, J =1.8 Hz, 1H), 7.15 (dd, J = 8.3, 1.8 Hz, 1H), 6.85 (d, J = 5.7 Hz, 1H),6.65 (t, J = 6.2 Hz, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.38 (d, J = 6.2Hz, 2H), 0.99 (s, 9H). HRMS (ESI) MS m/z calcd for C₂₃H₂₈N₇O [M + H]⁺418.2350, found 418.2352. Using 2,2-dimethylpropan-1-amine at 130° C.for 5 hours. 0.008 69 N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8- (tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8- diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.19 (s, 1H), 8.49 (s, 1H), 8.23-8.09 (m,2H), 7.90 (d, J = 0.8 Hz, 1H), 7.79 (d, J = 5.6 Hz, 1H), 7.28 (d, J =1.9 Hz, 1H), 7.22 (dd, J = 8.3, 1.8 Hz, 1H), 6.89 (d, J = 5.7 Hz, 1H),6.64 (d, J = 7.9 Hz, 1H), 4.29-4.16 (m, 1H), 3.96-3.84 (m, 8H), 3.49(td, J = 11.5, 2.2 Hz, 2H), 1.98 (br d, J = 14.0 Hz, 2H), 1.70-1.57 (m,2H). HRMS (ESI) MS m/z calcd for C₂₃H₂₆N₇O₂ [M + H]⁺ 432.2142, found432.2135. Using tetrahydro-2H-pyran-4-amine at 135° C. for 6 hours andpurification method B. 0.003 70 N8-(cyclohexylmethyl)-N2-(2-methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.17 (s, 1H), 8.45 (s, 1H), 8.18 (d, J =8.2 Hz, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.77 (d, J = 5.7 Hz, 1H), 7.28(d, J = 1.8 Hz, 1H), 7.18 (dd, J = 8.3, 1.8 Hz, 1H), 6.89-6.79 (m, 2H),3.94 (s, 3H), 3.88 (s, 3H), 3.38 (t, J = 6.4 Hz, 2H), 1.82-1.60 (m, 7H),1.29-1.12 (m, 2H), 1.08-0.96 (m, 2H). HRMS (ESI) MS m/z calcd forC₂₅H₃₀N₇O [M + H]⁺ 444.2506, found 444.2497. Using cyclohexylmethanamineat 130° C. for 8 hours. 0.061 71 1-((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4- yl)phenyl)amino)pyrido[3,4- d]pyrimidin-8-yl)amino)-2-methylpropan-2-ol  

¹H NMR (500 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.52 (s, 1H), 8.19 (d, J =8.2 Hz, 1H), 8.15 (s, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.76 (d, J = 5.7Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.17 (dd, J = 8.2, 1.8 Hz, 1H), 6.90(t, J = 5.6 Hz, 1H), 6.87 (d, J = 5.7 Hz, 1H), 4.89 (br s, 1H), 3.94 (s,3H), 3.88 (s, 3H), 3.48 (d, J = 5.6 Hz, 2H), 1.20 (s, 6H). HRMS (ESI) MSm/z calcd for C₂₂H₂₆N₇O₂ [M + H]⁺ 420.2142, found 420.2138. Using1-amino-2-methylpropan-2-ol at 130° C. for 8 hours and purificationmethod B. 0.006 72 N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8- (oxetan-3-ylmethyl)pyrido[3,4-d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.16 (s, 1H), 8.40 (s, 1H), 8.15 (s, 1H),7.96 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 0.9 Hz, 1H), 7.82 (d, J = 5.5 Hz,1H), 7.25 (d, J = 1.9 Hz, 1H), 7.18 (dd, J = 8.2, 1.9 Hz, 1H), 6.92 (d,J = 5.5 Hz, 1H), 4.78 (t, J = 5.2 Hz, 1H), 4.33 (br s, 2H), 4.06 (br s,2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.58 (t, J = 5.7 Hz, 2H), 2.84-2.73 (m,1H). HRMS (ESI MS m/z calcd for C₂₂H₂₄N₇O₂ [M + H]⁺ 418.1986, found418.1986. Using oxetan-3-yl-methanamine at 130° C. for 8 hours andpurification method B. 0.005 73 N8-(3,3-dimethylbutan-2-yl)-N2-(2-methoxy-4-(1-methyl- 1H-pyrazol-4- yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine

¹H NMR (500 MHz, DMSO-d₆): δ 9.17 (s, 1H), 8.62 (s, 1H), 8.17 (s, 1H),8.07 (d, J = 8.2 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J = 5.6 Hz, 1H), 7.29(d, J = 1.9 Hz, 1H), 7.15 (dd, J = 8.2, 1.9 Hz, 1H), 6.85 (d, J = 5.7Hz, 1H), 6.44 (d, J = 9.4 Hz, 1H), 4.18-4.04 (m, 1H), 3.93 (s, 3H), 3.88(s, 3H), 1.14 (d, J = 6.6 Hz, 3H), 0.99 (s, 9H). HRMS (ESI) MS m/z calcdfor C₂₄H₃₀N₇O [M + H]⁺ 432.2506, found 432.2503. Using3,3-dimethylbutan-2-amine at 140° C. for 18 hours. 0.012 743-((2-((2-methoxy-4-(1-methyl- 1H-pyrazol-4- yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)-2,2- dimethylpropan-1-ol  

¹H NMR (500 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.40 (s, 1H), 8.33 (d, J =8.3 Hz, 1H), 8.13 (s, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.76 (d, J = 5.7Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.24- 7.16 (m, 2H), 6.86 (d, J = 5.7Hz, 1H), 5.14 (t, J = 5.5 Hz, 1H), 3.95 (s, 3H), 3.89 (s, 3H), 3.45 (d,J = 5.9 Hz, 2H), 3.30 (d, J = 5.5 Hz, 2H), 0.94 (s, 6H). HRMS (ESI) MSm/z calcd for C₂₃H₂₈N₇O₂ [M + H]⁺ 434.2299, found 434.2296. Using3-amino-2,2-dimethylpropan-1-ol at 130° C. for 4 hours. 0.004 75N8-(1-cyclopropylethyl)- N2-(2-methoxy-4-(1-methyl- 1H-pyrazol-4-yl)phenyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, CDCl₃): δ 8.98 (s, 1H), 8.55 (d, J = 8.3 Hz, 1H), 7.97(s, 1H), 7.87 (d, J = 5.8 Hz, 1H), 7.79 (s, 1H), 7.64 (s, 1H), 7.17 (dd,J = 8.3, 1.8 Hz, 1H), 7.06 (d, J = 1.8 Hz, 1H), 6.74 (d, J = 5.9 Hz,1H), 6.50 (br d, J = 7.8 Hz, 1H), 4.02 (s, 3H), 3.99 (s, 3H), 3.91-3.81(m, 1H), 1.42 (d, J = 6.5 Hz, 3H), 1.18-1.08 (m, 1H), 0.67-0.54 (m, 2H),0.53-0.45 (m, 1H), 0.43-0.36 (m, 1H). HRMS (ESI) MS m/z calcd forC₂₃H₂₆N₇O [M + H]⁺ 416.2193, found 416.2189. Using1-cyclopropylethanamine at 130° C. for 8 hours and purification methodC. 0.004 76 (R)-N8-(3,3-dimethylbutan-2- yl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4- yl)phenyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.16 (s, 1H), 8.61 (s, 1H), 8.16 (d, J =0.9 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.76(d, J = 5.6 Hz, 1H), 7.28 (d, J = 1.9 Hz, 1H), 7.15 (dd, J = 8.2, 1.8Hz, 1H), 6.84 (d, J = 5.7 Hz, 1H), 6.44 (d, J = 9.5 Hz, 1H), 4.16-4.06(m, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 1.14 (d, J = 6.7 Hz, 3H), 0.98 (s,9H). HRMS (ESI) MS m/z calcd for C₂₄H₃₀N₇O [M + H]⁺ 432.2506, found432.2504. Using (R)-3,3-dimethylbutan-2-amine at 140° C. for 18 hours.0.009 77 (S)-N8-(3,3-dimethylbutan-2- yl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4- yl)phenyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.16 (s, 1H), 8.61 (s, 1H), 8.16 (d, J =0.9 Hz, 1H), 8.07 (d, J = 8.3 Hz, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.76(d, J = 5.6 Hz, 1H), 7.28 (d, J = 1.9 Hz, 1H), 7.15 (dd, J = 8.2, 1.8Hz, 1H), 6.84 (d, J = 5.7 Hz, 1H), 6.44 (d, J = 9.5 Hz, 1H), 4.16-4.06(m, 1H), 3.92 (s, 3H), 3.88 (s, 3H), 1.14 (d, J = 6.7 Hz, 3H), 0.98 (s,9H). HRMS (ESI) MS m/z calcd for C₂₄H₃₀N₇O [M + H]⁺ 432.2506, found432.2503. Using (S)-3,3-dimethylbutan-2-amine at 140° C. for 18 hours.0.005 78 N2-(2-methoxy-4-(1-methyl- 1H-pyrazol-4-yl)phenyl)-N8-(tetrahydrofuran-3- yl)pyrido[3,4-d]pyrimidine-2,8- diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.20 (s, 1H), 8.51 (s, 1H), 8.16 (s, 1H),8.14 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 0.8 Hz, 1H), 7.81 (d, J = 5.7 Hz,1H), 7.27 (d, J = 1.9 Hz, 1H), 7.21 (dd, J = 8.2, 1.9 Hz, 1H), 6.93 (d,J = 5.7 Hz, 1H), 6.78 (br d, J = 6.8 Hz, 1H), 4.68-4.58 (m, 1H),3.98-3.85 (m, 8H), 3.82-3.75 (m, 1H), 3.68 (dd, J = 8.9, 3.9 Hz, 1H),2.36- 2.25 (m, 1H), 2.03-1.93 (m, 1H). HRMS (ESI) MS m/z calcd forC₂₂H₂₄N₇O₂ [M + H]⁺ 418.1986, found 418.1983. Usingtetrahydrofuran-3-amine at 140° C. for 24 hours and purification methodB. 0.008 79 N2-(2-methoxy-4-(1-methyl- 1H-pyrazol-4-yl)phenyl)-N8-((tetrahydrofuran-3- yl)methyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.24-9.15 (m, 1H), 8.38 (s, 1H), 8.27 (d, J= 8.2 Hz, 1H), 8.15 (d, J = 0.9 Hz, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.80(d, J = 5.6 Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.21 (dd, J = 8.3, 1.8Hz, 1H), 7.08 (t, J = 5.8 Hz, 1H), 6.88 (d, J = 5.7 Hz, 1H), 3.95 (s,3H), 3.88 (s, 3H), 3.81 (td, J = 8.1, 5.6 Hz, 1H), 3.73 (dd, J = 8.5,7.0 Hz, 1H), 3.65 (td, J = 7.9, 6.7 Hz, 1H), 3.58 (dd, J = 8.5, 5.1 Hz,1H), 3.53 (ddd, J = 7.1, 5.9, 1.6 Hz, 2H), 2.74-2.64 (m, 1H), 2.05-1.95(m, 1H), 1.68 (dddd, J = 12.2, 7.9, 6.8, 5.6 Hz, 1H). HRMS (ESI) MS m/zcalcd for C₂₃H₂₆N₇O₂ [M + H]⁺ 432.2142, found 432.2137. Using(tetrahydrofuran-3-yl)methanamine at 135° C. for 18 hours andpurification method B. 0.005 80 1-(2-(2-methoxy-4-(1-methyl-1H-pyrazol-4- yl)phenylamino)pyrido[3,4-d]pyrimidin-8-yl)pyrrolidin-3-ol  

¹H NMR (500 MHz, DMSO-d₆): δ 9.14 (s, 1H), 8.39 (s, 1H), 8.15 (d, J =0.9 Hz, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 7.83(d, J = 5.4 Hz, 1H), 7.25 (d, J = 1.9 Hz, 1H), 7.18 (dd, J = 8.2, 1.9Hz, 1H), 6.87 (d, J = 5.4 Hz, 1H), 4.87 (d, J = 3.4 Hz, 1H), 4.32 (br s,1H), 3.96-3.83 (m, 9H), 3.78 (d, J = 12.5 Hz, 1H), 1.97-1.88 (m, 1H),1.87- 1.80 (m, 1H). HRMS (ESI) MS m/z calcd for C₂₂H₂₄N₇O₂ [M + H]⁺418.1986, found 418.1982. Using pyrrolidin-3-ol at 135° C. for 7 hoursand purification method A. 0.006 81 N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8- methyl-N8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.21 1H), 8.54 (s, 1H), 8.17 (d, J = 0.8Hz, 1H), 7.97-7.84 (m, 3H), 7.27 (d, J = 1.9 Hz, 1H), 7.15 (dd, J = 8.2,1.8 Hz, 1H), 7.08 (d, J = 5.3 Hz, 1H), 4.95 (tt, J = 11.7, 3.9 Hz, 1H),3.89 (s, 3H), 3.88 (s, 3H), 3.78 (dd, J = 11.1, 4.2 Hz, 2H), 3.13-3.04(m, 2H), 3.01 (s, 3H), 1.81 (qd, J = 12.1, 4.5 Hz, 2H), 1.61-1.52 (m,2H). HRMS (ESI) MS m/z calcd for C₂₄H₂₈N₇O₂ [M + H]+ 446.2299, found446.2295. Using N-methyltetrahydro-2H-pyran-4-amine 135° C. for 17 hoursand purification method A. 0.033 82 N8-tert-butyl-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4- yl)phenyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.15 (s, 1H), 8.57 (s, 1H), 8.17 (d, J =1.0 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 0.8 Hz, 1H), 7.79(d, J = 5.7 Hz, 1H), 7.28 (d, J = 1.9 Hz, 1H), 7.20 (dd, J = 8.3, 1.9Hz, 1H), 6.85 (d, J = 5.7 Hz, 1H), 6.48 (s, 1H), 3.93 (s, 3H), 3.88 (s,3H), 1.52 (s, 9H). HRMS (ESI) MS m/z calcd for C₂₂H₂₆N₇O [M + H]⁺404.2193, found 404.2191 Using 2-methylpropan-2-amine at 140° C. for 7days. 0.025 83 N2-(2-methoxy-4-(1-methyl- 1H-pyrazol-4-yl)phenyl)-N8-(1-methylcyclohexyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.15 (s, 1H), 8.61 (s, 1H), 8.17 (d, J =0.8 Hz, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 0.8 Hz, 1H), 7.75(d, J = 5.7 Hz, 1H), 7.29 (d, J = 1.9 Hz, 1H), 7.16 (dd, J = 8.2, 1.8Hz, 1H), 6.84 (d, J = 5.7 Hz, 1H), 6.48 (s, 1H), 3.92 (s, 3H), 3.88 (s,3H), 2.34-2.24 (m, 2H), 1.62-1.37 (m, 9H), 1.32-1.19 (m, 2H). HRMS (ESI)MS m/z calcd for C₂₅H₃₀N₇O [M + H]⁺ 444.2506, found 444.2521. Using1-methylcyclohexanamine hydrochloride at 130° C. for 7 days andpurification method C. 0.019 84 N8-(2,2-difluoropropyl)-N2-(2-methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.21 (s, 1H), 8.52 (s, 1H), 8.21-8.12 (m,2H), 7.88 (d, J = 0.9 Hz, 1H), 7.81 (d, J = 5.6 Hz, 1H), 7.27 (d, J =1.9 Hz, 1H), 7.18 (dd, J = 8.2, 1.9 Hz, 1H), 7.00 (t, J = 6.3 Hz, 1H),6.97 (d, J = 5.6 Hz, 1H), 4.05 (td, J = 14.2, 6.6 Hz, 2H), 3.92 (s, 3H),3.87 (s, 3H), 1.66 (t, J = 19.0 Hz, 3H). ¹⁹F NMR (471 MHz, DMSO-d₆): δ−94.22 (s). HRMS (ESI) MS m/z calcd for C₂₁H₂₂F₂N₇O [M + H]⁺ 426.1848,found 426.1842. Using 2,2-difluoropropan-1-amine hydrochloride at 140°C. for 24 hours. 0.014 85 N8-(3-methoxy-2,2- dimethylpropyl)-N2-(2-methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2-8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.16 (s, 1H), 8.50 (s, 1H), 8.17-8.11 (m,2H), 7.87 (d, J = 0.8 Hz, 1H), 7.76 (d, J = 5.7 Hz, 1H), 7.28 (d, J =1.9 Hz, 1H), 7.16 (dd, J = 8.2, 1.9 Hz, 1H), 6.84 (d, J = 5.6 Hz, 2H),3.93 (s, 3H), 3.87 (s, 3H), 3.45 (d, J = 5.9 Hz, 2H), 3.22 (s, 3H), 3.20(s, 2H), 0.95 (s, 6H). HRMS (ESI) MS m/z calcd for C₂₄H₃₀N₇O₂ [M + H]⁺448.2455, found 448.2451. Using 3-methoxy-2,2-dimethylpropan-1- aminehydrochloride for 2 hours. 0.024 86 N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy- 4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.57 (s, 1H), 8.17 (d, J =0.9 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.77(d, J = 5.6 Hz, 1H), 7.29 (d, J = 1.9 Hz, 1H), 7.15 (dd, J = 8.2, 1.9Hz, 1H), 6.88 (d, J = 5.7 Hz, 1H), 6.67 (t, J = 5.5 Hz, 1H), 3.93 (s,3H), 3.88 (s, 3H), 3.55 (d, J = 5.5 Hz, 2H), 3.22 (s, 3H), 1.19 (s, 6H).HRMS (ESI) MS m/z calcd for C₂₃H₂₈N₇O₂ [M + H]⁺ 434.2299, found434.2296. Using 2-methoxy-2-methylpropan-1-amine for 24 hours. 0.005 87N2-(2-methoxy-4-(1-methyl- 1H-pyrazol-4-yl)phenyl)-N8-(2,2,2-trifluoroethyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.24 (s, 1H), 8.46 (s, 1H), 8.24 (d, J =8.2 Hz, 1H), 8.15 (s, 1H), 7.88 (d, J = 0.9 Hz, 1H), 7.85 (d, J = 5.6Hz, 1H), 7.33 (t, J = 6.6 Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.20 (dd, J= 8.2, 1.9 Hz, 1H), 7.04 (d, J = 5.7 Hz, 1H), 4.48-4.32 (m, 2H), 3.93(s, 3H), 3.87 (s, 3H). ¹⁹F NMR (471 MHz, DMSO-d₆): δ −70.33 (s). HRMS(ESI) MS m/z calcd for C₂₀H₁₉F₃N₇O [M + H]⁺ 430.1598, found 430.1593.Using 2,2,2-trifluoroethanamine, trifluoroacetic acid and2,2,2-trifluoroethanol instead of N-methyl-2-pyrrolidinone at 130° C.for 6 hours. 0.075 88 N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(2-oxa- 6-azaspiro[3.4]octan-6-yl)pyrido[3,4-d]pyrimidin-2- amine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.13 (s, 1H), 8.53 (s, 1H), 8.14 (s, 1H),7.87 (s, 1H), 7.81 (d, J = 5.5 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.26(d, J = 2.0 Hz, 1H), 7.19 (d, J = 7.9 Hz, 1H), 6.88 (d, J = 5.4 Hz, 1H),4.48 (s, 4H), 4.08 (s, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.77-3.66 (m,2H), 2.18-2.07 (m, 2H). HRMS (ESI) MS m/z calcd for C₂₄H₂₆N₇O₂ [M + H]⁺444.2142, found 444.2137. Using (2-oxa-6-azaspiro[3,4]octan-6-amine at130°C. for 4 hours and purification method B. 0.003 891-((2-(2-methoxy-4-(1-methyl- 1H-pyrazol-4- yl)phenylamino)pyrido[3,4-d]pyrimidin-8- ylamino)methyl)cyclobutanol  

¹H NMR (500 MHz, DMSO-d₆): δ 9.16 (s, 1H), 8.51 (s, 1H), 8.21-8.06 (m,2H), 7.87 (d, J = 0.8 Hz, 1H), 7.76 (d, J = 5.7 Hz, 1H), 7.26 (d, J =1.9 Hz, 1H), 7.16 (dd, J = 8.2, 1.9 Hz, 1H), 6.92-6.74 (m, 2H), 5.60 (s,1H), 3.92 (s, 3H), 3.87 (s, 3H), 3.62 (d, J = 5.4 Hz, 2H), 2.05-1.98 (m,4H), 1.70-1.62 (m, 1H), 1.59-1.48 (m, 1H). HRMS (ESI) MS m/z calcd forC₂₃H₂₆N₇O₂ [M + H]⁺ 432.2142, found 432.2161. Using1-(aminomethyl)cyclobutanol at 130° C. for 4 hours and purificationmethod B. 0.007

Example 908-(cyclohexylthio)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine

A mixture of8-chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine(Example 94, 26 mg, 0.071 mmol) and potassium carbonate (15 mg, 0.109mmol) in DMF (0.35 mL) was treated with cyclohexanethiol (12 μL, 0.098mmol) and stirred at room temperature for 4 days. An additional batch ofpotassium carbonate (10 mg, 0.07 mmol) and thiol (12 μL, 0.098 mmol)were added and the mixture stirred at 50° C. for 18 hours. The reactionwas quenched with brine and extracted with EtOAc. The combined organiclayers were washed with water and brine, dried and concentrated. Theresidue was purified by silica gel column chromatography eluting with 0to 80% EtOAc in cyclohexane to give the title compound (30 mg, 94%).

¹H NMR (500 MHz, DMSO-d₆): δ 9.35 (s, 1H), 8.55 (br s, 1H), 8.29 (d,J=5.4 Hz, 1H), 8.20 (d, J=0.9 Hz, 1H), 7.93 (d, J=0.8 Hz, 1H), 7.48 (d,J=5.4 Hz, 1H), 7.29 (d, J=1.9 Hz, 1H), 7.26 (dd, J=8.2, 1.9 Hz, 1H),3.96 (br s, 4H), 3.87 (s, 3H), 2.17-2.05 (m, 2H), 1.82-1.72 (m, 2H),1.69-1.59 (m, 1H), 1.59-1.40 (m, 4H), 1.39-1.28 (m, 1H).

HRMS (ESI) MS m/z calcd for C₂₄H₂₇N₆OS [M+H]⁺ 447.1962, found 447.1948.

MPS1 IC50 (μM): 0.234

Example 918-(1-ethyl-1H-pyrazol-4-yl)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine

A solution of8-chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine(Example 94, 35 mg, 0.095 mmol),1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (32mg, 0.144 mmol) and Pd(dppf)Cl₂.DCM (8 mg, 9.79 μmol) was dissolved inTHF (0.6 mL) and 2M sodium carbonate in water (0.2 mL) and heated to 65°C. for 18 hours. The mixture was diluted with DCM and quenched withsaturated aqueous NaHCO₃. The aqueous layer was extracted with DCM threetimes. The combined organic layers were dried and concentrated. Theresidue was purified by silica gel column chromatography eluting with 0to 5% MeOH in EtOAc to give the title compound (28 mg, 68%).

¹H NMR (500 MHz, DMSO-d₆): δ 9.35 (s, 1H), 9.10 (s, 1H), 8.50 (s, 1H),8.33 (d, J=5.2 Hz, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 7.96 (d, J=0.9 Hz,1H), 7.67 (d, J=8.1 Hz, 1H), 7.56 (d, J=5.3 Hz, 1H), 7.37 (d, J=1.9 Hz,1H), 7.28 (dd, J=8.0, 1.9 Hz, 1H), 3.99 (q, J=7.1 Hz, 2H), 3.90 (s, 3H),3.84 (s, 3H), 1.22 (t, J=7.2 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₂₃H₂₃N₈O [M+H]⁺ 427.1989, found 427.1967.

MPS1 IC50 (μM): 0.010

Example 928-(1-isopropyl-1H-pyrazol-4-yl)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine

The title compound was prepared according to the method described forExample 91 using1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.After heating to 65° C. for 18 hours, an additional batch of catalyst (8mg, 9.79 μmol) and boronic ester (17 mg, 0.07) were added, and themixture heated to 65° C. for 3 hours.

¹H NMR (500 MHz, DMSO-d₆): δ 9.36 (s, 1H), 9.10 (s, 1H), 8.50 (br s,1H), 8.34 (d, J=5.2 Hz, 1H), 8.23 (s, 2H), 7.96 (d, J=0.9 Hz, 1H), 7.67(d, J=8.1 Hz, 1H), 7.57 (d, J=5.3 Hz, 1H), 7.38 (d, J=1.9 Hz, 1H), 7.27(dd, J=8.2, 1.9 Hz, 1H), 4.37-4.25 (m, 1H), 3.91 (s, 3H), 3.84 (s, 3H),1.29 (d, J=6.7 Hz, 6H).

HRMS (ESI) MS m/z calcd for C₂₄H₂₅N₈O [M+H]⁺ 441.2146, found 441.2122.

MPS1 IC50 (μM): 0.014

Example 938-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine

The title compound was prepared according to the method described forExample 91 using1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(Preparation 112). The residue was purified by silica gel columnchromatography eluting with 0 to 80% EtOAc in cyclohexane to give thetitle compound (18 mg, 41%).

¹H NMR (500 MHz, DMSO-d₆): δ 9.39 (s, 1H), 9.10 (s, 1H), 8.63 (s, 1H),8.44-8.32 (m, 2H), 8.21 (d, J=0.9 Hz, 1H), 7.94 (d, J=0.8 Hz, 1H), 7.73(d, J=8.1 Hz, 1H), 7.62 (d, J=5.2 Hz, 1H), 7.36 (d, J=1.8 Hz, 1H), 7.27(dd, J=8.0, 1.8 Hz, 1H), 6.50-6.18 (m, 1H), 4.50 (t, J=14.2 Hz, 2H),3.90 (s, 3H), 3.86 (s, 3H). ¹⁹F NMR (471 MHz, DMSO) δ −122.71 (d, J=54.8Hz).

HRMS (ESI) MS m/z calcd for C₂₃H₂₁F₂N₈O [M+H]⁺ 463.1801, found 463.1808.

MPS1 IC50 (μM): 0.010

Example 948-chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine

A solution of N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide(Preparation 56, 24 mg, 0.104 mmol) in THF (1 mL) was treated withsodium hydride (7 mg, 0.175 mmol) at 0° C. After stirring for 20 minutesat room temperature the mixture was cooled to 0° C. and8-chloro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 97, 33mg, 0.135 mmol) was added. The reaction was allowed to reach roomtemperature and stirred for 18 hours. Aqueous NaOH (2M, 0.5 mL) and MeOH(0.5 mL) were added and the resulting mixture stirred for 1 hour. Thevolatiles were removed under reduced pressure and the residue waspartitioned between EtOAc and water. The aqueous layer was extractedwith EtOAc and the combined organic layers were washed with water,brine, dried and concentrated. The residue was purified by silica gelcolumn chromatography eluting with 0 to 80% EtOAc in cyclohexane to givethe title compound (30 mg, 79%).

¹H NMR (500 MHz, DMSO): δ 9.47 (s, 1H), 8.84 (s, 1H), 8.51 (br s, 1H),8.25 (d, J=5.2 Hz, 1H), 8.18 (s, 1H), 7.92 (s, 1H), 7.86 (d, J=5.2 Hz,1H), 7.30 (d, J=1.9 Hz, 1H), 7.26 (dd, J=8.3, 1.9 Hz, 1H), 3.95 (s, 3H),3.87 (s, 3H).

LCMS (ESI) Rt=2.81 minutes MS m/z 367 [M+H]⁺

MPS1 IC50 (μM): 0.164

Example 958-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine

To a solution of8-chloro-N-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine(Preparation 113, 12 mg, 0.034 mmol) in 1,4-dioxane (2 mL) and water (1mL) was added 1-methylpyrazole-4-boronic acid pinacol ester (14 mg,0.068 mmol), cesium carbonate (17 mg, 0.051 mmol) and Pd(PPh₃)₄ (2 mg,1.71 umol). The reaction mixture was heated to 100° C. under microwaveirradiation for 30 minutes. The reaction mixture was diluted with EtOAc(20 mL) and water (20 mL). The organic layer was washed with water (20mL) and brine (20 mL), dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluting with0-15% MeOH in EtOAc to give the title compound (7 mg, 52%).

¹H NMR (500 MHz, CDCl₃): δ 9.16 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.40(d, J=5.5 Hz, 2H), 7.86 (d, J=8.0 Hz, 1H), 7.82 (s, 1H), 7.67 (s, 1H),7.50-7.45 (m, 2H), 7.36 (d, J=5.5 Hz, 1H), 7.05 (br s, 1H), 4.00 (s,3H), 3.77 (s, 3H), 2.39 (s, 3H).

HRMS (ESI) MS m/z calcd for C₂₂H₂₀N₈ [M+H]⁺ 397.1884, found 397.1878;

LCMS (ESI) Rt=2.37 minutes MS m/z 397.05 [M+H]⁺

MPS1 IC50 (μM): 0.021

Example 96N-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine

The title compound was prepared according to the method described forExample 95 using

8-chloro-N-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine(Preparation 114) and 1-Methylpyrazole-4-boronic acid pinacol ester.

¹H NMR (500 MHz, CDCl₃): δ 9.16 (s, 1H), 8.72 (s, 1H), 8.60 (d, J=8.0Hz, 1H), 8.54 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 7.90 (br s, 1H), 7.77 (d,J=0.5 Hz, 1H), 7.63 (s, 1H), 7.38 (d, J=5.5 Hz, 1H), 7.17 (dd, J=8.0,2.0 Hz, 1H), 7.07 (m, 1H), 4.23 (q, J=7.0 Hz, 2H), 3.99 (s, 3H), 3.98(s, 3H), 1.54 (t, J=7.0 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₂₃H₂₂N₈O [M+H]⁺ 427.1989, found 427.1984.

LCMS (ESI) RT=2.66 minutes MS m/z 427.03 [M+H]⁺

MPS1 IC50 (μM): 0.008

Example 97N-(2-isopropoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine

The title compound was prepared according to the method described forExample 95 using8-chloro-N-(2-isopropoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine(Preparation 115) and 1-methylpyrazole-4-boronic acid pinacol ester.

¹H NMR (500 MHz, CDCl₃): δ 9.16 (s, 1H), 8.73 (s, 1H), 8.63 (d, J=9.0Hz, 1H), 8.54 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 7.92 (br s, 1H), 7.76 (d,J=0.5 Hz, 1H), 7.63 (s, 1H), 7.38 (d, J=5.5 Hz, 1H), 7.16 (dd, J=9.0,2.0 Hz, 1H), 7.09 (d, J=2.0 Hz, 1H), 4.74 (quin, J=6.0 Hz, 1H), 4.00 (s,3H), 3.99 (s, 3H), 1.47 (s, 3H), 1.46 (s, 3H).

HRMS (ESI) MS m/z calcd for C₂₄H₂₄N₈O [M+H]⁺ 441.2146, found 441.2139.

LCMS (ESI) Rt=2.75 minutes MS m/z 441.05 [M+H]⁺

MPS1 IC50 (μM): 0.049

Example 98N-(2-(2-methoxyethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine

The title compound was prepared according to the method described forExample 95 using8-chloro-N-(2-(2-methoxyethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine(Preparation 116) and 1-methylpyrazole-4-boronic acid pinacol ester.

¹H NMR (500 MHz, CDCl₃): δ 9.16 (s, 1H), 8.71 (s, 1H), 8.59 (d, J=8.5Hz, 1H), 8.53 (s, 1H), 8.45 (d, J=5.5 Hz, 1H), 8.10 (br s, 1H), 7.77 (d,J=0.5 Hz, 1H), 7.63 (s, 1H), 7.38 (d, J=5.5 Hz, 1H), 7.21 (dd, J=8.0,2.0 Hz, 1H), 7.14 (d, J=2.0 Hz, 1H), 4.32-4.30 (m, 2H), 3.99 (s, 6H),3.84-3.82 (m, 2H), 3.51 (s, 3H).

HRMS (ESI) MS m/z calcd for C₂₃H₂₄N₈O₂ [M+H]⁺ 457.2095, found 457.2089

LCMS (ESI) Rt=2.45 minutes MS m/z 457.02 [M+H]⁺

MPS1 IC50 (μM): 0.146

Example 99N8-(cyclopropylmethyl)-N2-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine

To a solution of8-chloro-N-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine(Preparation 113, 40 mg, 0.114 mmol) in NMP (3 mL) was addedcyclopropanemethylamine (0.1 ml, 1.140 mmol). The reaction mixture washeated to 120° C. for 18 hours. The reaction mixture was diluted withaqueous saturated NaHCO₃ (20 mL) and EtOAc (2×20 mL). The combinedorganic layers were washed with water (30 mL) and brine (30 mL), dried(MgSO₄) and concentrated in vacuo. The residue was purified by silicagel column chromatography eluting with 0-5% MeOH in EtOAc to give thetitle compound (4.2 mg, 10%).

¹H NMR (500 MHz, CDCl₃): δ 8.96 (s, 1H), 8.11 (d, J=9.0 Hz, 1H), 7.88(d, J=5.5 Hz, 1H), 7.62 (s, 1H), 7.41-7.38 (m, 2H), 7.06 (br s, 1H),6.74 (d, J=5.5 Hz, 1H), 6.51 (br t, J=5.5 Hz, 2H), 3.98 (s, 3H), 3.45(dd, J=7.0, 5.5 Hz, 2H), 2.40 (s, 3H), 1.21 (m, 1H), 0.60 (ddd, J=8.0,5.5, 5.0 Hz, 2H), 0.37-0.34 (m, 2H).

HRMS (ESI) MS m/z calcd for C₂₂H₂₃N₇ [M+H]⁺ 386.2088, found 386.2083.

LCMS (ESI) Rt=1.81 minutes MS m/z 386.10 [M+H]⁺

MPS1 IC50 (μM): 0.008

Example 100N8-cyclohexyl-N2-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine

The title compound was prepared according to the method described forExample 99 using cyclohexylamine.

¹H NMR (500 MHz, CDCl₃): δ 8.95 (s, 1H), 8.12 (d, J=8.5 Hz, 1H), 7.88(d, J=6.0 Hz, 1H), 7.79 (s, 1H), 7.63 (s, 1H), 7.40-7.38 (m, 2H), 7.04(br s, 1H), 6.72 (d, J=5.0 Hz, 1H), 6.40 (br d, J=8.5 Hz, 1H), 3.98 (s,3H), 2.41 (s, 3H), 2.23 (m, 1H), 2.14-2.09 (m, 2H), 1.81-1.77 (m, 2H),1.71-1.62 (m, 2H), 1.46-1.28 (m, 4H).

HRMS (ESI) MS m/z calcd for C₂₄H₂₇N₇ [M+H]⁺ 414.2401, found 414.2398.

LCMS (ESI) Rt=2.03 minutes MS m/z 414.08 [M+H]⁺

MPS1 IC50 (μM): no data

Example 101N8-(cyclopropylmethyl)-N2-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine

The title compound was prepared according to the method described for

Example 99 using8-chloro-N-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine(Preparation 114) and cyclopropanemethylamine for 5 hours. The residuewas further purified by passage through a SCX-2 cartridge eluting with100% MeOH-0.5 M NH₃ in MeOH to give the title compound (2.6 mg, 5%).

¹H NMR (500 MHz, CDCl₃): δ 8.99 (s, 1H), 8.57 (d, J=8.5 Hz, 1H), 7.99(br s, 1H), 7.90 (d, J=6.0 Hz, 1H), 7.77 (s, 1H), 7.62 (s, 1H), 7.15(dd, J=8.5, 2.0 Hz, 1H), 7.04 (d, J=2.0 Hz, 1H), 6.77 (d, J=6.0 Hz, 1H),6.58 (br s, 1H), 4.23 (q, J=7.0 Hz, 2H), 3.98 (s, 3H), 3.50 (t, J=6.0Hz, 2H), 1.56 (t, J=7.0 Hz, 3H), 1.27 (m, 1H), 0.65 (ddd, J=8.0, 5.0,4.0 Hz, 2H), 0.40 (app q, J=5.0 Hz, 2H).

HRMS (ESI) MS m/z calcd for C₂₃H₂₅N₇O [M+H]⁺ 416.2193, found 416.2185.

LCMS (ESI) Rt=2.13 minutes MS m/z 416.08 [M+H]⁺

MPS1 IC50 (μM): 0.049

Example 102N2-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine

The title compound was prepared according to the method described forExample 99 using8-chloro-N-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine(Preparation 114) and 4-aminotetrahydropyran. The residue was furtherpurified by passage through a SCX-2 cartridge eluting with 100% MeOH—1MNH₃ in MeOH to give the title compound (3 mg, 9%).

¹H NMR (500 MHz, CDCl₃): δ 8.99 (s, 1H), 8.51 (d, J=8.0 Hz, 1H), 7.98(br s, 1H), 7.89 (d, J=5.5 Hz, 1H), 7.77 (d, J=0.5 Hz, 1H), 7.64 (s,1H), 7.16 (dd, J=8.0, 2.0 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 6.78 (d,J=5.5 Hz, 1H), 6.40 (br d, J=8.0 Hz, 1H), 4.37 (br s, 1H), 4.24 (q,J=7.0 Hz, 2H), 4.08 (dt, J=11.0, 3.0 Hz, 2H), 3.99 (s, 3H), 3.68 (td,J=11.0, 2.0 Hz, 2H), 2.21-2.17 (m, 2H), 1.76-1.67 (m, 3H), 1.56 (t,J=7.0 Hz, 3H).

HRMS (ESI) MS m/z calcd for C₂₄H₂₇N₇O₂ [M+H]⁺ 446.2299, found 446.2299.

LCMS (ESI) Rt=2.16 minutes MS m/z 446.01 [M+H]⁺

MPS1 IC50 (μM): 0.010

Example 103N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(1-methyl-1H-pyrazol-4-yl)-2,6-naphthyridin-3-amine

Method 6

To a solution of 5-(1-methyl-1H-pyrazol-4-yl)-2,6-naphthyridin-3-yltrifluoromethanesulfonate (Preparation 90, 7 mg, 0.020 mmol) in1,4-dioxane (1.5 ml) was added2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline (Preparation 19, 5 mg,0.023 mmol), cesium carbonate (9 mg, 0.028 mmol), xantphos (0.51 mg,0.879 umol) and Pd(dba)₂ (1 mg, 1.1739 umol). The reaction mixture washeated to 100° C. for 1 hr. The reaction mixture was filtered throughCelite® and concentrated in vacuo. The residue was purified by silicagel column chromatography eluting with 50-100% EtOAc in cyclohexanefollowed by 10% MeOH in EtOAc. The residue was passed through a SCX-2cartridge eluting with 100% MeOH followed by 1M NH₃ in MeOH, to give thetitle compound (2.2 mg, 27%).

¹H NMR (500 MHz, CDCl₃): δ 9.05 (d, J=5.5 Hz, 1H), 8.40 (d, J=5.5 Hz,1H), 8.03 (s, 1H), 7.96 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.76 (d, J=1.0Hz, 1H), 7.63-7.62 (m, 2H), 7.51 (dd, J=5.5, 1.0 Hz, 1H), 7.17 (br s,1H), 7.15 (dd, J=8.0, 2.0 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H), 4.03 (s, 3H),3.98 (d, J=1.0 Hz, 6H).

HRMS (ESI) MS m/z calcd for C₂₃H₂₁N₇O [M+H]⁺ 412.1880, found 412.1876;

LCMS (ESI) Rt=2.30 minutes MS m/z 412.07 [M+H]⁺

MPS1 IC50 (μM): 0.012

Example 104N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-2,6-naphthyridin-3-amine

The title compound was prepared according to Method 6 (Example 103)using 4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyaniline (Preparation18) for 18 hours. The residue was purified using silica gel columnchromatography eluting with 0-20% MeOH in EtOAc.

¹H NMR (500 MHz, CDCl₃): δ 9.09 (s, 1H), 8.43 (d, J=5.5 Hz, 1H), 8.04(s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.66 (s, 1H), 7.54 (dd,J=5.5, 1.0 Hz, 1H), 7.01 (dd, J=8.0, 2.0 Hz, 1H), 6.97 (s, 1H), 6.94 (d,J=2.0 Hz, 1H), 4.04 (s, 3H), 3.97 (s, 3H), 3.58 (s, 3H), 2.48 (s, 3H).

HRMS (ESI) MS m/z calcd for C₂₄H₂₃N₇O [M+H]⁺ 426.2037, found 426.2029;

LCMS (ESI) Rt=1.62 minutes MS m/z 426.05 [M+H]⁺

MPS1 IC50 (μM): 0.007

Example 105N1-cyclohexyl-N7-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-2,6-naphthyridine-1,7-diamine

The title compound was prepared according to Method 6 (Example 103)using 5-(cyclohexylamino)-2,6-naphthyridin-3-yltrifluoromethanesulfonate (Preparation 93) and2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline (Preparation 19) for 18hours. The residue was purified using silica gel column chromatographyeluting with 0-10% MeOH in DCM.

¹H NMR (500 MHz, CDCl₃): δ 8.83 (s, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.87(d, J=6.0 Hz, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 7.14 (dd, J=8.5, 2.0 Hz,1H), 7.06-7.04 (m, 2H), 6.98 (s, 1H), 6.88 (d, J=6.0 Hz, 1H), 4.86 (m,1H), 3.97 (s, 6H), 2.19-2.14 (m, 4H), 1.82-1.77 (m, 3H), 1.74-1.67 (m,3H).

HRMS (ESI) MS m/z calcd for C₂₅H₂₈N₆O [M+H]⁺ 429.2397, found 429.2394;

LCMS (ESI) Rt=2.02 minutes MS m/z 429.07 [M+H]⁺

MPS1 IC50 (μM): 0.056

Example 106N1-(cyclopropylmethyl)-N7-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-2,6-naphthyridine-1,7-diamine

The title compound was prepared according to Method 6 (Example 103)using 5-((cyclopropylmethyl)amino)-2,6-naphthyridin-3-yltrifluoromethanesulfonate (Preparation 96) and2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline (Preparation 19) for 3hours. The residue was purified using silica gel column chromatographyeluting with 0-10% MeOH in DCM.

¹H NMR (500 MHz, CDCl₃): δ 8.85 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.87(d, J=5.5 Hz, 1H), 7.62 (s, 1H), 7.14 (dd, J=8.0, 2.0 Hz, 1H), 7.08 (brs, 1H), 7.06 (dd, J=5.5, 2.0 Hz, 1H), 6.93 (t, J=5.5 Hz, 1H), 5.13 (m,1H), 3.98 (s, 6H), 3.46-3.42 (m, 2H), 1.24-1.18 (m, 2H), 0.63-0.59 (m,2H).

HRMS (ESI) MS m/z calcd for C₂₃H₂₄N₆O [M+H]⁺ 401.2084, found 401.2077;

LCMS (ESI) Rt=1.89 minutes MS m/z 401.06 [M+H]⁺

MPS1 IC50 (μM): 0.082

Example 107N-(2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenylamino)pyrido[3,4-d]pyrimidin-8-yl)-2-methylpropane-2-sulfonamide

A mixture of8-chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine(Example 94, 27 mg, 0.074 mmol), tell-butylsulfonamide (13 mg, 0.095mmol), tris(dibenzylideneacetone)dipalladium(0) (2 mg, 2.183 μmol),cesium carbonate (34 mg, 0.104 mmol) and DavePhos (3 mg, 7.61 μmol) in1,4-dioxane (0.7 mL) (degassed) was stirred at 100° C. for 18 hours. Thereaction was quenched with water and extracted with EtOAc. The combinedorganic layers were washed with brine, dried and concentrated in vacuoThe residue was purified by silica gel column chromatography elutingwith 0 to 90% EtOAc in cyclohexane to give the title compound (29 mg,85%).

¹H NMR (500 MHz, DMSO-d₆): δ 11.97 (s, 1H), 9.17 (s, 1H), 8.84 (br. s,1H), 8.50 (s, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 7.36 (d, J=7.0 Hz, 1H),7.27 (d, J=1.9 Hz, 1H), 7.06 (dd, J=8.4, 1.8 Hz, 1H), 6.89 (d, J=6.9 Hz,1H), 3.96 (s, 3H), 3.88 (s, 3H), 1.48 (s, 9H).

HRMS (ESI) MS m/z calcd for C₂₂H₂₆N₇O₃S [M+H]⁺ 468.1812, found 468.1808.

MPS1 IC50 (μM): 0.039

The following Examples were prepared according to Method 5 (Example 54)above using8-chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine(Example 94) and the appropriate amine as described. The crude reactionresidues were purified as above or according to one of the followingmethods:

-   Method A: Silica gel column chromatography eluting with 0-5% or    0-10% MeOH in DCM.-   Method B: Silica gel column chromatography eluting with 0-5% MeOH in    EtOAc.-   Method C: Silica gel column chromatography eluting with 0-70% EtOAc    in cyclohexane followed by reverse phase preparative HPLC eluting    with 10-90% MeOH in water (0.1% formic acid).-   Method D: Silica gel column chromatography eluting with 0-100% EtOAc    in cyclohexane followed by a second chromatography eluting with    either 0-5% or 0-20% MeOH in either DCM or EtOAc.-   Method E: Silica gel column chromatography eluting with between    0-20% MeOH in DCM.-   Method F: Elution through an SCX-2 column followed by silica gel    column chromatography eluting with 0-5% MeOH in EtOAc.-   Method G: Elution through an SCX-2 column followed by silica gel    column chromatography eluting with 1-10% MeOH/aq NH₃ (10/1) in DCM.-   Method I: Elution through an SCX-2 column using 1M followed by 7M    methanolic ammonia followed by trituration with MeOH.-   Method J: Elution through an SCX-2 column followed by silica gel    column chromatography eluting with 0-10% EtOH in DCM.-   Method K: Trituration with ether.-   Method L: Elution through an SCX column using 50% MeOH in chloroform    followed by 50% chloroform in 7N NH₃/MeOH.

MPS1 Example IC50 No Name/Structure Data (μM) 108N²-(2-methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-N⁸,N⁸-dimethylpyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.21 (s, 1H), 8.47 (s, 1H), 8.20-8.13 (m,1H), 8.05 (d, J = 8.2 Hz, 1H), 7.91 (d, J = 5.4 Hz, 1H), 7.90 (d, J =0.8 Hz, 1H), 7.27 (d, J = 1.8 Hz, 1H), 7.22 (dd, J = 8.2, 1.9 Hz, 1H),7.05 (d, J = 5.4 Hz, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.27 (s, 6H). HRMS(ESI) MS m/z calcd for C₂₀H₂₂N₇O [M + H]⁺ 376.1880, found 376.1876.Using 2M dimethylamine in THF at 100° C. for 5 hours. 0.016 109N²-(2-methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-N⁸-((3-methyloxetan-3- yl)methyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.15 (s, 1H), 8.38 (s, 1H), 8.15 (d, J =0.8 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.81(d, J = 5.5 Hz, 1H), 7.25 (d, J = 1.8 Hz, 1H), 7.16 (dd, J = 8.2, 1.9Hz, 1H), 6.90 (d, J = 5.5 Hz, 1H), 4.90 (t, J = 5.3 Hz, 1H), 4.17 (br.s, 2H), 3.97-3.80 (m, 8H), 3.43 (d, J = 5.3 Hz, 2H), 1.25 (s, 3H). HRMS(ESI) MS m/z calcd for C₂₃H₂₆N₇O₂ [M + H]⁺ 432.2142, found 432.2137.Using (3-methyloxetan-3-yl)methanamine at 130-for 8 hours andpurification method B. 0.002 110 N²-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N⁸- methylpyrido[3,4-d]pyrimidine- 2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.37 (d, J = 8.3 Hz, 1H),8.30 (s, 1H), 8.14 (d, J = 0.9 Hz, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.82(d, J = 5.6 Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.23 (dd, J = 8.3, 1.9Hz, 1H), 7.06-6.99 (m, 1H), 6.86 (d, J = 5.6 Hz, 1H), 3.95 (s, 3H), 3.88(s, 3H), 3.03 (d, J = 4.8 Hz, 3H). HRMS (ESI) MS m/z calcd for C₁₉H₂₀N₇O[M + H]⁺ 362.1724, found 362.1746. Using 2M methylamine in THF at 100°C. for 10 hours. 0.017 111 N²-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N⁸- (oxetan-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO): δ 8.78 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 8.24(s, 1H), 8.14 (s, 1H), 7.88 (s, 1H), 7.24 (d, J = 1.9 Hz, 1H), 7.18 (dd,J = 8.4, 1.9 Hz, 1H), 7.10 (d, J = 7.0 Hz, 1H), 5.99 (d, J = 7.0 Hz,1H), 4.82 (br. s, 1H), 4.31-4.19 (m, 1H), 4.11 (t, J = 11.0 Hz, 1H),3.99-3.91 (m, 4H), 3.87 (s, 3H), 3.64-3.55 (m, 1H), 3.48- 3.40 (m, 1H).HRMS (ESI) m/z calcd for C₂₁H₂₂N₇O₂ [M + H]⁺ 404.1829, found 404.1827.Using oxetan-3-amine at 130° C. for 3 hours and purification methodD. >1 112 1-((2-(2-methoxy-4-(1-methyl- 1H-pyrazol-4-yl)phenylamino)pyrido[3,4- d]pyrimidin-8- ylamino)methyl)cyclopropanol  

¹H NMR (500 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.51 (s, 1H), 8.23-8.09 (m,2H), 7.88 (d, J = 0.8 Hz, 1H), 7.76 (d, J = 5.7 Hz, 1H), 7.28 (d, J =1.9 Hz, 1H), 7.18 (dd, J = 8.2, 1.9 Hz, 1H), 6.96 (t, J = 5.5 Hz, 1H),6.88 (d, J = 5.7 Hz, 1H), 5.67 (s, 1H), 3.94 (s, 3H), 3.88 (s, 3H), 3.63(d, J = 5.4 Hz, 2H), 0.68-0.63 (m, 2H), 0.62-0.58 (m, 2H). HRMS (ESI) MSm/z calcd for C₂₂H₂₄N₇O₂ [M + H]⁺ 418.1986, found 418.1995. Using1-(aminomethyl)cyclopropanol at 130° C. for 6 hours. 0.005 113N²-(2-methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-N⁸-(1-methylpiperidin-4-yl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.51 (s, 1H), 8.17 (s, 1H),8.13 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 0.8 Hz, 1H), 7.79 (d, J = 5.7 Hz,1H), 7.28 (d, J = 1.9 Hz, 1H), 7.21 (dd, J = 8.3, 1.8 Hz, 1H), 6.88 (d,J = 5.7 Hz, 1H), 6.60 (br. d, J = 7.5 Hz, 1H), 4.03 (br. s, 1H), 3.93(s, 3H), 3.88 (s, 3H), 2.82 (br. s, 2H), 2.30 (br. s, 5H), 2.08-1.95(br. m, 2H), 1.76-1.57 (br. m, 2H). HRMS (ESI) MS m/z calcd forC₂₄H₂₉N₈O [M + H]⁺ 445.2459, found 445.2458. Using1-methylpiperidin-4-amine at 130° C. for 10 hours and purificationmethod E. 0.009 114 2-(2-(2-methoxy-4-(1-methyl- 1H-pyrazol-4-yl)phenylamino)pyrido[3,4- d]pyrimidin-8-ylamino)-2- methylpropan-1-ol  

¹H NMR (500 MHz, DMSO-d₆): δ 9.16 (s, 1H), 8.47 (s, 1H), 8.23 (d, J =8.2 Hz, 1H), 8.15 (s, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.77 (d, J = 5.7Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.21 (dd, J = 8.2, 1.9 Hz, 1H), 6.91(s, 1H), 6.87 (d, J = 5.7 Hz, 1H), 5.38 (t, J = 5.1 Hz, 1H), 3.94 (s,3H), 3.88 (s, 3H), 3.59 (d, J = 5.1 Hz, 2H), 1.46 (s, 6H). HRMS (ESI) MSm/z calcd for C₂₂H₂₆N₇O₂ [M + H]⁺ 420.2142, found 420.2146. Using2-amino-2-methylpropan-1-ol neat at 130° C. for 36 hours. 0.017 115N-(2-methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-8-(2-oxa-6-azaspiro[3.3]heptan-6- yl)pyrido[3,4-d]pyrimidin-2- amine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.45 (s, 1H), 8.18 (d, J =0.9 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 0.8 Hz, 1H), 7.84(d, J = 5.5 Hz, 1H), 7.33-7.18 (m, 2H), 6.97 (d, J = 5.4 Hz, 1H), 4.73(s, 4H), 4.46 (s, 4H), 3.92 (s, 3H), 3.89 (s, 3H). HRMS (ESI) MS m/zcalcd for C₂₃H₂₄N₇O₂ [M + H]⁺ 430.1986, found 430.1990. Using2-oxa-6-azaspiro[3.3]heptane oxalate and triethylamine at 130’ for 6hours and purification method B. 0.003 116 N²-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8- (oxetan-2-ylmethyl)pyrido[3,4-d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.20 (s, 1H), 8.49 (s, 1H), 8.18 (d, J =8.2 Hz, 1H), 8.16 (d, J = 0.9 Hz, 1H), 7.89 (d, J = 0.8 Hz, 1H), 7.79(d, J = 5.6 Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.18 (dd, J = 8.2, 1.9Hz, 1H), 7.01 (t, J = 5.9 Hz, 1H), 6.91 (d, J = 5.6 Hz, 1H), 5.01 (ddd,J = 12.2, 7.1, 5.2 Hz, 1H), 4.56 (ddd, J = 8.5, 7.3, 5.8 Hz, 1H), 4.46(dt, J = 9.1, 5.9 Hz, 1H), 3.93 (s, 3H), 3.88 (s, 3H), 3.87-3.78 (m,1H), 3.71 (dt, J = 13.9, 5.0 Hz, 1H), 2.68-2.60 (m, 1H), 2.49- 2.43 (m,1H). HRMS (ESI) MS m/z calcd for C₂₂H₂₄N₇O₂ [M + H]⁺ 418.1986, found418.1990. Using oxetan-2-ylmethanamine at 130° C. for 11 hours andpurification method B. 0.008 117 N²-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N⁸-((3- methyltetrahydrofuran-3-yl)methyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.18 (d, J = 0.9 Hz, 1H), 8.48 (s, 1H),8.22 (d, J = 8.3 Hz, 1H), 8.15 (s, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.78(d, J = 5.6 Hz, 1H), 7.28 (d, J = 1.8 Hz, 1H), 7.17 (dd, J = 8.2, 1.8Hz, 1H), 6.88 (dd, J = 5.6, 0.9 Hz, 2H), 3.94 (s, 3H), 3.88 (s, 3H),3.87-3.83 (m, 1H), 3.78 (td, J = 8.3, 6.8 Hz, 1H), 3.70 (d, J = 8.5 Hz,1H), 3.63-3.52 (m, 2H), 3.34 (s, 1H), 1.92 (ddd, J = 12.5, 8.3, 6.8 Hz,1H), 1.65 (ddd, J = 12.2, 8.1, 5.6 Hz, 1H), 1.16 (s, 3H). HRMS (ESI) MSm/z calcd for C₂₄H₂₈N₇O₂ [M + H]⁺ 446.2299, found 446.2321. Using(3-methyltetrahydrofuran-3- yl)methanamine at 135° C. for 16 hours.0.003 118 4-(2-((2-methoxy-4-(1-methyl- 1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4- d]pyrimidin-8-yl)thiomorpholine 1,1-dioxide 

¹H NMR (500 MHz, DMSO-d₆): δ 9.29 (s, 1H), 8.76 (s, 1H), 8.19 (d, J =0.9 Hz, 1H), 7.98 (d, J = 5.4 Hz, 1H), 7.92 (d, J = 0.8 Hz, 1H), 7.84(d, J = 8.1 Hz, 1H), 7.30 (d, J = 1.8 Hz, 1H), 7.27 (d, J = 5.4 Hz, 1H),7.25 (dd, J = 8.1, 1.9 Hz, 1H), 4.31 (s, 4H), 3.89 (s, 6H), 3.17 (s,4H). HRMS (ESI) MS m/z calcd for C₂₂H₂₄N₇O₃S [M + H]⁺ 466.1656, found466.1647. Using thiomorpholine 1,1-dioxide at 135° C. for 18 hours.0.011 119 N-(2-methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-8-(7-oxa-2-azaspiro[3.5]nonan-2- yl)pyrido[3,4-d]pyrimidin-2- amine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.15 (s, 1H), 8.52 (s, 1H), 8.15 (s, 1H),7.88 (d, J = 0.8 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 5.5 Hz,1H), 7.26 (d, J = 1.8 Hz, 1H), 7.17 (dd, J = 8.2, 1.8 Hz, 1H), 6.91 (d,J = 5.5 Hz, 1H), 4.01 (s, 4H), 3.89 (d, J = 2.0 Hz, 6H), 3.50 (s, 4H),1.72 (t, J = 5.1 Hz, 4H). HRMS (ESI) MS m/z calcd for C₂₅H₂₈N₇O₂ [M +H]⁺ 458.2299, found 458.2289. Using N-methyl-2-pyrrolidinone at 135° C.for 3 hours and purification method D. 0.003 120N-(2-methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-8-(6-oxa-2-azaspiro[3.4]octan-2- yl)pyrido[3,4-d]pyrimidin-2- amine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.17 (s, 1H), 8.48 (s, 1H), 8.15 (d, J =0.9 Hz, 1H), 7.91-7.86 (m, 2H), 7.83 (d, J = 5.5 Hz, 1H), 7.25 (d, J =1.8 Hz, 1H), 7.17 (dd, J = 8.2, 1.8 Hz, 1H), 6.96 (d, J = 5.5 Hz, 1H),4.25 (s, 4H), 3.90 (s, 3H), 3.88 (s, 3H), 3.81 (s, 2H), 3.71 (t, J = 6.9Hz, 2H), 2.14 (t, J = 6.9 Hz, 2H). HRMS (ESI) MS m/z calcd forC₂₄H₂₆N₇O₂ [M + H]⁺ 444.2142, found 444.2127 Using6-oxa-2-azaspiro[3.4]octane oxalate and triethylamine at 135° C. for 2hours and purification method D. 0.003 121 1-(2-(2-methoxy-4-(1-methyl-1H-pyrazol-4- yl)phenylamino)pyrido[3,4- d]pyrimidin-8-yl)azetidine-3-carbonitrile  

¹H NMR (500 MHz, DMSO-d₆): δ 9.21 (s, 1H), 8.61 (s, 1H), 8.16 (d, J =0.8 Hz, 1H), 7.89 (s, 1H), 7.87 (d, J = 5.5 Hz, 1H), 7.82 (d, J = 8.2Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H), 7.20 (dd, J = 8.2, 1.8 Hz, 1H), 7.07(d, J = 5.5 Hz, 1H), 4.54 (t, J = 8.8 Hz, 2H), 4.42- 4.32 (m, 2H), 3.90(s, 3H), 3.89-3.84 (m, 4H). HRMS (ESI) MS m/z calcd for C₂₂H₂₁N₈O [M +H]⁺ 413.1833, found 413.1817. Using azetidine-3-carbonitrilehydrochloride and triethylamine at 135° C. for 8 hours. 0.008 122N-(2-methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-8-(2-oxa-7-azaspiro[4.4]nonan-7- yl)pyrido[3,4-d]pyrimidin-2- amine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.12 (s, 1H), 8.51 (s, 1H), 8.14 (d, J =0.8 Hz, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.81 (d, J = 5.4 Hz, 1H), 7.72(d, J = 8.1 Hz, 1H), 7.25 (d, J = 1.9 Hz, 1H), 7.16 (dd, J = 8.1, 1.8Hz, 1H), 6.88 (d, J = 5.4 Hz, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 3.86-3.66(m, 6H), 3.58-3.46 (m, 2H), 1.88-1.78 (m, 4H). HRMS (ESI) MS m/z calcdfor C₂₅H₂₈N₇O₂ [M + H]⁺ 458.2299, found 458.2292. Using2-oxa-7-azaspiro[4.4]nonane at 135° C. for 2 hours. 0.003 123N-(2-methoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-8-(2-oxa-6-azaspiro[3.5]nonan-6- yl)pyrido[3,4-d]pyrimidin-2- amine  

¹H NMR (500 MHz, MeOD): δ 9.17 (s, 1H), 8.44 (d, J = 8.1 Hz, 1H),8.05-7.94 (m, 1H), 7.87 (s, 1H), 7.24 (s, 1H), 7.19 (d, J = 5.4 Hz, 1H),7.19-7.12 (m, 1H), 6.98 (s, 1H), 4.09-3.99 (m, 5H), 3.99-3.91 (m, 5H),3.87-3.77 (m, 2H), 2.84 (t, J = 7.4 Hz, 1H), 2.59 (t, J = 7.4 Hz, 1H),2.06- 1.94 (m, 2H), 1.90-1.78 (m, 2H). HRMS (ESI) MS m/z calcd forC₂₅H₂₈N₇O₂ [M + H]⁺ 458.2299, found 458.2299. Using2-oxa-6-azaspiro[3.5]nonane at 135° C. for 24 hours. 0.011 124N⁸-((3-fluorooxetan-3- yl)methyl)-N²-(2-methoxy-4-(1-methyl-1H-pyrazol-4- yl)phenyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, MeOD): δ 9.22 (s, 1H), 8.21 (d, J = 8.3 Hz, 1H), 8.02(s, 1H), 7.87 (d, J =0 0.9 Hz, 1H), 7.49 (d, J = 7.1 Hz, 1H), 7.30-7.24(m, 2H), 7.20 (d, J = 7.1 Hz, 1H), 4.01 (s, 2H), 3.97 (s, 2H), 3.62 (s,6H), 3.44-3.20 (m, 2H). HRMS (ESI) MS m/z calcd for C₂₂H₂₃FN₇O₂ [M + H]⁺436.1892, found 436.1887. Using (3-fluorooxetan-3-yl)methanamine and TFAin 2,2,2-trifluoroethanol at 130° C. for 7 hours and purification methodE. >1 125 Racemic N²-(2-methoxy-4-(1- methyl-1H-pyrazol-4-yl)phenyl)-N⁸-(1- (tetrahydrofuran-3- yl)ethyl)pyrido[3.4-d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.49 (s, 1H), 8.44 (s, 1H),8.16 (dd, J = 33.1, 8.3 Hz, 1Ha), 8.16 (d, J = 6.4 Hz, 1Hb), 7.89 (dd, J= 7.2, 0.8 Hz, 1H), 7.78 (dd, J = 5.6, 4.7 Hz, 1H), 7.28 (dd, J = 3.6,1.8 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.87 (dd, J = 5.7, 1.4 Hz, 1H),6.68 (dd, J = 23.9, 8.6 Hz, 1H), 4.30-4.18 (m, 1H), 3.94 (s, 3Ha), 3.93(s, 3Hb), 3.88 (s, 3H), 3.86- 3.71 (m, 2H), 3.70-3.59 (m, 1H), 3.51-3.43 (m, 1H), 2.60-2.53 (m, 1H), 2.07- 1.95 (m, 1H), 1.69 (ddd, J =19.6, 12.2, 7.6 Hz, 1H), 1.25 (d, J = 6.5 Hz, 3Ha), 1.22 (d, J = 6.5 Hz,3Hb). HRMS (ESI) MS m/z calcd for C₂₄H₂₈N₇O₂ [M + H]⁺ 446.2299, found446.2288. Using racemic 1-(tetrahydrofuran-3- yl)ethanamine at 135° C.for 24 hours. 0.003 126 2-(2-(2-Methoxy-4-(1-methyl- 1H-pyrazol-4-yl)phenylamino)pyrido[3,4- d]pyrimidin-8-ylamino)ethanol  

¹H NMR (500 MHz, CD₃OD): δ 8.92 (s, 1H), 8.34 (d, J = 8.3Hz, 1H), 7.86(d, J = 0.8 Hz, 1H), 7.78 (d, J = 0.8Hz, 1H), 7.66 (d, J = 5.8 Hz, 1H),7.12 (dd, J = 8.3, 1.9 Hz, 1H), 7.07 (d, J = 1.9 Hz, 1H), 6.76 (d, J =5.8 Hz, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.87 (dd, J = 5.8, 4.9 Hz, 2H),3.67 (dd, J = 5.8, 4.9 Hz, 2H). HRMS (ESI) MS m/z calcd for C₂₀H₂₂N₇O₂[M + H]⁺ 392.1819, found: 392.1819. Using ethanolamine at 130° C. for 5hours and purification method F. 0.011 127 N²-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N⁸-(2- methoxyethyl)pyrido[3,4-d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, CD₃OD): δ 8.98 (d, J = 1.7 Hz, 1H). 8.33 (d, J = 8.1Hz, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.70 (d, J = 5.7 Hz, 1H), 7.13 (m,2H), 6.81 (d, J = 5.7 Hz, 1H), 3.98 (s, 3H), 3.94 (s, 3H), 3.71 (s, 4H),3.49 (s, 3H). HRMS (ESI) MS m/z calcd for C₂₁H₂₄N₇O₂ [M + H]⁺ 406.1986,found: 406.1979. Using 2-methoxyethylamine at 130° C. for 5 hours andpurification method F. 0.008 128 Racemic 1-(2-(2-Methoxy-4-(1-methyl-1H-pyrazol-4- yl)phenylamino)pyrido[3,4-d]pyrimidin-8-ylamino)propan- 2-ol  

¹H NMR (500 MHz, CD₃OD): δ 8.98 (s, 1H), 8.41 (d, J = 8.3 Hz, 1H), 7.91(s, 1H), 7.81 (s, 1H), 7.69 (d, J = 5.7 Hz, 1H), 7.18 (d, J = 8.3 Hz,1H), 7.13 (s, 1H), 6.80 (d, J = 5.7 Hz, 1H), 4.04-4.14 (m, 1H), 3.98 (s,3H), 3.94 (s, 3H), 3.70 (dd, J = 13.5, 3.6 Hz, 1H), 3.37 (dd, J = 13.5,7.6 Hz, 1H), 1.31 (d, J = 6.2 Hz, 3H). HRMS (ESI) MS m/z calcd forC₂₁H₂₄N₇O₂ [M + H]⁺ 406.1986, found 406.1978. Using Racemic1-aminopropan-2-ol at 130° C. for 5 hours and purification method F.0.008 129 Racemic 2-(2-(2-Methoxy-4-(1- methyl-1H-pyrazol-4-yl)phenylamino)pyrido[3.4- d]pyrimidin-8-ylamino)propan-1-ol  

¹H NMR (500 MHz, CD₃OD): δ 8.92 (s, 1H), 8.32 (d, J = 8.3Hz, 1H), 7.86(d, J = 0.8 Hz, 1H), 7.77 (d, J = 0.8 Hz, 1H), 7.66 (d, J = 5.8 Hz, 1H),7.11 (dd, J = 8.3, 1.9 Hz, 1H), 7.07 (d, J = 1.9 Hz, 1H), 6.75 (d, J =5.8 Hz, 1H), 4.22 (qt, J = 6.6, 4.5 Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H),3.78 (dd, J = 10.9, 4.5 Hz, 1H), 3.72 (dd, J = 10.9, 4.5 Hz, 1H), 1.37(d, J = 6.6 Hz, 3H), HRMS (ESI) MS m/z calcd for C₂₁H₂₄N₇O₂ [M + H]⁺406.1986, found 406.1976. Using DL-alaninol and triethylamine at 130° C.for 1.5 hours. 0.007 130 2-(2-(2-Methoxy-4-(1-methyl- 1H-pyrazol-4-yl)phenylamino)pyrido[3,4- d]pyrimidin-8- ylamino)propane-1,3-diol  

¹H NMR (500 MHz, CD₃OD): δ 9.07 (s, 1H), 8.49 (d, J = 8.3 Hz, 1H), 7.96(d, J = 0.8 Hz, 1H), 7.84 (d, J = 0.8 Hz, 1H), 7.75 (d, J = 5.8 Hz, 1H),7.23 (dd, J = 8.3, 1.9 Hz, 1H), 7.21 (d, J = 1.9 Hz, 1H), 6.89 (d, J =5.8 Hz, 1H), 4.20 (quin, J = 5.2 Hz, 1H), 4.02 (s, 3H), 3.95 (s, 3H),3.89 (dd, J = 11.0, 5.2 Hz, 2H), 3.83 (dd, J = 11.0, 5.2 Hz, 2H). HRMS(ESI) MS m/z calcd for C₂₁H₂₄N₇O₃ [M + H]⁺ 422.1935, found 422.1929Using 2-aminopropane-1,3-diol and triethylamine in DMA at 130° C. for 4hours and purification method G. 0.004 131 3-Methoxy-2-(2-(2-methoxy-4-(1-methyl-1H-pyrazol-4- yl)phenylamino)pyrido[3,4-d]pyrimidin-8-ylamino)propan-1-ol  

¹H NMR (500 MHz, CD₃OD): δ 9.04 (s, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.94(d, J = 0.8 Hz, 1H), 7.82 (d, J = 0.8 Hz, 1H), 7.74 (d, J = 5.8 Hz, 1H),7.17-7.20 (m, 2H), 6.86 (d, J = 5.8 Hz, 1H), 4.31 (tt, J = 5.6, 4.4 Hz,1H), 4.01 (s, 3H), 3.95 (s, 3H), 3.88 (dd, J = 10.9, 4.4 Hz, 1H),3.75-3.81 (m, 2H), 3.66 (dd, J = 9.4, 5.6 Hz, 1H), 3.48 (s, 3H). HRMS(ESI) MS m/z calcd for C₂₂H₂₆N₇O₃ [M + H]⁺ 436.2092, found 436.2085.Using 2-amino-3-methoxypropan-1-ol and triethylamine at 130° C. for 5hours followed by purification method F. 0.004 132(3-((2-(2-Methoxy-4-(1-methyl- 1H-pyrazol-4-yl)phenylamino)pyrido[3,4-d]pyrimidin-8- ylamino)methyl)oxetan-3- yl)methanol  

¹H NMR (500 MHz, DMSO-d₆): δ 8.75 (s, 1H), 8.43 (d, J = 8.2 Hz, 1H),8.16 (s, 1H), 8.14 (s, 1H), 7.88 (s, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.18(dd, J = 8.2, 2.0 Hz, 1H), 6.83 (d, J = 7.3 Hz, 1H), 6.08 (d, J = 7.3Hz, 1H), 4.75 (m, 2H), 3.94 (s, 3H), 3.87 (s, 3H), 3.68 (s, 2H), 3.40(s, 2H), 3.34 (s, 4H). HRMS (ESI) MS m/z calcd for C₂₃H₂₆N₇O₃ [M + H]⁺448.2092, found 448.2086. Using (3-(aminomethyl)oxetan-3- yl)methanol at130° C. for 3 hours and purification method I. >1 133(1-(2-(2-Methoxy-4-(1-methyl- 1H-pyrazol-4- yl)phenylamino)pyrido[3,4-d]pyrimidin-8-yl)pyrrolidin-3- yl)methanol  

¹H NMR (500 MHz, CDCl₃): δ 8.94 (s, 1H), 8.29 (d, J = 8.3 Hz, 1H), 7.94(d, J = 5.5 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H), 7.73 (s, 1H), 7.61 (d, J= 0.8 Hz, 1H), 7.12 (dd, J = 8.3, 1.9 Hz, 1H), 7.00 (d, J = 1.9 Hz, 1H),6.75 (d, J = 5.5 Hz, 1H), 4.21 (dd, J = 11.7, 7.4 Hz, 1H), 4.14 (ddd, J= 11.9, 7.9, 4.2 Hz, 1H), 3.98-4.05 (m, 1H), 3.97 (s, 3H), 3.97 (s, 3H),3.89 (dd, J = 11.7, 7.4 Hz, 1H), 3.76 (d, J = 6.7 Hz, 2H), 2.52-2.63 (m,1H), 2.16 (dtd, J = 11.8, 7.0, 4.2 Hz, 1H), 1.97 (br s, 1H), 1.82 (dq, J= 11.8, 7.9 Hz, 1H). HRMS (ESI) MS m/z calcd for C₂₃H₂₆N₇O₂ [M + H]⁺432.2142, found 432.2150. Using pyrrolidin-3-ylmethanol andtriethylamine at 130° C. for 4.5 hours and purification method J. 0.003134 (1-(2-(2-Methoxy-4-(1-methyl- 1H-pyrazol-4-yl)phenylamino)pyrido[3,4- d]pyrimidin-8-yl)piperidin-3- yl)methanol  

¹H NMR (500 MHz, CDCl₃): δ 9.04 (s, 1H), 8.65 (d, J = 8.3 Hz, 1H), 8.01(s, 1H), 8.00 (d, J = 5.5 Hz, 1H), 7.79 (d, J = 0.8 Hz, 1H), 7.65 (d, J= 0.8 Hz, 1H), 7.19 (dd, J = 8.3, 1.9 Hz, 1H), 7.03 (d, J = 1.9 Hz, 1H),6.97 (d, J = 5.5 Hz, 1H), 4.12-4.21 (m, 1H), 3.97- 4.09 (m, 2H), 4.00(s, 3H), 3.98 (s, 3H), 3.56-3.71 (m, 3H), 3.61 (br s, 1H), 2.14- 2.23(m, 1H), 2.00 (ddt, J = 12.4, 8.2, 4.4 Hz, 1H), 1.65-1.88 (m, 2H),1.43-1.52 (m, 1H). HRMS (ESI) MS m/z calcd for C₂₄H₂₈N₇O₂ [M + H]+446.2299, found 446.2303. Using piperidin-3-ylmethanol and triethylamineat 130° C. for 4.5 hours and purification method J. 0.004 135(4-(2-(2-Methoxy-4-(1-methyl- 1H-pyrazol-4- yl)phenylamino)pyrido[3,4-d]pyrimidin-8-yl)morpholin-2- yl)methanol  

¹H NMR (500 MHz, CDCl₃): δ 9.07 (s, 1H), 8.61 (d, J = 8.2 Hz, 1H), 8.07(d, J = 5.4 Hz, 1H), 8.04 (s, 1H), 7.79 (d, J = 0.8 Hz, 1H), 7.68 (d, J= 0.8 Hz, 1H), 7.19 (dd, J = 8.2, 1.8 Hz, 1H), 7.08 (d, J = 5.4 Hz, 1H),7.05 (d, J = 1.8 Hz, 1H), 4.56-4.65 (m, 2H), 4.17 (ddd, J = 11.4, 3.4,1.7 Hz, 1H), 4.06-4.13 (m, 2H), 4.01 (s, 3H), 3.98 (s, 3H), 3.67- 3.81(m, 2H), 3.22 (ddd, J = 12.8, 11.4, 3.4 Hz, 1H), 2.96 (dd, J = 12.5,10.4 Hz, 1H), 2.20 (d, J = 6.5 Hz, 1H). HRMS (ESI) MS m/z calcd forC₂₃H₂₆N₇O₃ [M + H]⁺ 448.2092. found 448.2098. Usingmorpholin-2-ylmethanol and triethylamine at 130° C. for 4.5 hours andpurification method J. 0.004 136 6-Cyclopropyl-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4- yl)phenyl)-8-(2-oxa-6- azaspiro[3.4]octan-6-yl)pyrido[3,4-d]pyrimidin-2- amine  

¹H NMR (500 MHz, CDCl₃): δ 8.90 (s, 1H), 8.29 (br d, J = 7.25 Hz, 1H),7.76 (s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.12 (dd, J = 1.89, 8.20 Hz,1H), 7.03 (s, 1H), 6.70 (s, 1H), 4.75 (m, 2H), 4.68 (m, 2H), 4.30 (br s,2H), 3.99 (s, 3H), 3.97 (s, 3H), 3.95 (br, 2H), 2.26 (t, J = 6.62 Hz,2H), 1.98 (br s, 1H), 1.07 (br s, 2H), 0.89 (br s, 2H). HRMS (ESI) calcdfor C₂₇H₃₀N₇O₂ [M + H]⁺ 484.2456, found 484.2453. Using8-Chloro-6-cyclopropyl-N-(2- methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine (Preparation 125) and 2-oxa-6-azaspiro[3.4]octane at 130° C. for 3 hours and purification method K.0.093 137 Racemic N-(2-Methoxy-4-(1- methyl-1H-pyrazol-4-yl)phenyl)-8-(2- methylmorpholino)pyrido[3,4- d]pyrimidin-2-amine  

¹H NMR (500 MHz, CDCl₃): δ 9.06 (s, 1H), 8.6 (d, J = 8.3 Hz, 1H), 8.07(d J = 5.5 Hz, 1H), 8.04 (s, 1H), 7.77 (s, 1H), 7.63 (s, 1H), 7.13 (dd,J = 8.3, 1.8 Hz, 1H), 7.05 (d, J = 5.4 Hz, 1H), 7.04 (d, J = 1.8 Hz,1H), 4.59 (d, J = 12 Hz, 2H), 4.16-4.1 (m, 3H), 4 (s, 3H), 3.98 (s, 3H),3.18-3.16 (m, 1H), 2.81- 2.79 (m, 1H), 1.26 (d, J = 6.3 Hz, 3H). HRMS(ESI) calcd for C₂₃H₂₅N₇NaO₂ [M + H]⁺ 454.1962, found 454.1956. Usingracemic 2-methylmorpholine hydrochloride with triethylamine at 135° C.for 18 hours and purification method B. 0.007 138N-(2-Methoxy-4-1-methyl-1H- pyrazol-4-yl)phenyl)-8-(4-methoxypiperidin-1- yl)pyrido[3,4-d]pyrimidin-2- amine  

¹H NMR (500 MHz, CDCl₃); δ 9.04 (s, 1H), 8.06 (s, 1H), 8.05 (d, J = 5.4Hz, 1H), 7.77 (s, 1H), 7.64 (s, 1H), 7.17 (dd, J = 8.3, 1.8 Hz, 1H),7.03 (d, J = 1,8 Hz, 1H), 7.01 (d, J = 5.4 Hz, 1H), 4.44-4.42 (m, 2H), 4(s, 3H), 3.98 (s, 3H), 3.52-3.5 (m, 1H), 3.46 (s, 3H), 3.39-3.41 (m,2H), 2.2-2.18 (m, 2H), 1.92-1.9 (m, 2H). HRMS (ESI) calcd for C₂₄H₂₈N₇O₂[M + H]⁺ 446.2299, found 446.229. Using 4-methoxypiperidinehydrochloride with triethylamine at 135° C. for 18 hours andpurification method L. 0.008 139 N-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(4- (methylsulfonyl)pjperazin-1-yl)pyrido[3,4-d]pyrimidin-2- amine  

¹H NMR (500 MHz, CDCl₃): δ 9.08 (s, 1H), 8.48 (d, J = 7.1 Hz, 1H), 8.06(d, J = 5.4 Hz, 1H), 1H), 7.99 (s, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 7.09(dd, J = 5.4, 1.8 Hz, 2H), 7.05 (d, J = 1.8 Hz, 1H), 4.08 (br, s, 2H), 4(s, 3H), 3.98 (s, 3H), 3.51 (t, J = 5 Hz, 2H), 2.86 (s, 3H), 2.39-2.37(m, 1H), 2.06-2.04 (m, 1H), 1.61 (br s, 2H). HRMS (ESI) calcd forC₂₃H₂₇N₈O₃S [M + H]⁺ 495.1921, found 495.1914. Using1-(methylsulfonyl)piperazine at 135° C. for 18 hours and purificationmethod L. 0.006 140 1-(2-(2-Methoxy-4-(1-methyl- 1H-pyrazol-4-yl)phenylamino)pyrido[3,4- d]pyrimidin-8-yl)piperidine-4- carbonitrile  

¹H NMR (500 MHz, CDCl₃): δ 9.05 (s, 1H), 8.59 (d, J = 8.3 Hz, 1H), 8.05(d, J = 5.5 Hz, 1H), 8.04 (s, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 7.14 (dd,J = 8.3, 1.8 Hz, 1H), 7.06 (d, J = 5.4 Hz, 1H), 7.04 (d, J = 1.8 Hz,1H), 4.27- 4.24 (m, 2H), 4 (s, 3H), 3.98 (s, 3H), 3.67 (br, s, 2H),2.95-2.93 (m, 1H), 2.23-2.17 (m, 4H). HRMS (ESI) calcd for C₂₄H₂₅N₈O[M + H]⁺ 441.2146, found 441.2138. Using 4-cyanopiperidine at 135° C.for 18 hours and purification method L. 0.004

Examples 141 and 142(S)-N²-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N⁸-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamineand(R)-N²-(2-methoxy-4-(1-methyl-1-pyrazol-4-yl)phenyl)-N⁸-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine

The title compounds were separated by Preparative HPLC (chiralpak IA90/10 MeCN/IPA (0.1% diethylamine)) from racemicN2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine(Example 117).

Example 141(S)-N²-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N⁸-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine

LCMS (ESI) Rt=2.35 minutes MS m/z 446 [M+H]⁺, 99% ee

MPS1 IC50 (μM): 0.003

Example 142(R)-N²-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N⁸-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine

LCMS (ESI) Rt=2.36 minutes MS m/z 446 [M+H]⁺, 97% ee

MPS1 IC50 (μM): 0.003

Example 143(±)-N-(2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenylamino)pyrido[3,4-d]pyrimidin-8-yl)-2-methylpropane-2-sulfinamide

A mixture of8-chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine(Example 94, 27 mg, 0.074 mmol), (±)-2-methyl-2-propanesulfinamide (12mg, 0.099 mmol), palladium(II) acetate (1 mg, 4.44 μmol), cesiumcarbonate (48 mg, 0.147 mmol) and Xantphos (5 mg, 8.64 μmol) in1,4-dioxane (0.7 mL) (degassed) was stirred at 100° C. for 18 hours. Thereaction was quenched with water and extracted with EtOAc. The combinedorganic layers were washed with brine, dried and concentrated in vacuo.The residue was purified by silica gel column chromatography elutingwith 0 to 90% EtOAc in cyclohexane to give the title compound (14 mg,42%).

¹H NMR (500 MHz, DMSO-d₆): δ 9.35 (s, 1H), 9.01 (s, 1H), 8.19 (d, J=1.0Hz, 1H), 8.08 (s, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.95-7.91 (m, 2H), 7.36(d, J=5.6 Hz, 1H), 7.30 (d, J=1.9 Hz, 1H), 7.17 (dd, J=8.2, 1.8 Hz, 1H),3.90 (s, 3H), 3.89 (s, 3H), 1.27 (s, 9H).

HRMS (ESI) MS m/z calcd for C₂₂H₂₆N₇O₂S [M+H]⁺ 452.1863, found 452.1856.

MPS1 IC50 (μM): 0.005

Example 1448-(3,6-Dihydro-2H-pyran-4-yl)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine

The title compound was prepared according to the method described forExample 91 using8-chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine(Example 94) and2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

¹H NMR (500 MHz, CDCl₃): δ 9.14 (s, 1H), 8.8 (d, J=8.3 Hz, 1H), 8.46 (d,J=5.3 Hz, 1H), 8.07 (s, 1H), 7.77 (s, 1H), 7.64 (s, 1H), 7.42 (d, J=5.3,1H), 7.17-7.13 (m, 2H), 7.03 (d, J=1.8 Hz, 1H), 4.53 (q, J=2.7 Hz, 2H),4.07 (t, J=5.4 Hz, 2H), 4 (s, 3H), 3.98 (s, 3H), 2.9-2.88 (m, 2H).

HRMS (ESI) calcd for C₂₃H₂₃N₆O₂ [M+H]⁺ 415.1877, found 415.1875

MPS1 IC50 (μM): 0.005

The following Examples were prepared according to Method 5 (Example 54)above using8-chloro-N-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)pyrido[3,4-d]pyrimidin-2-amine(Preparation 117) and the appropriate amine as described. The crudereaction residues were purified as described or according to one of thefollowing methods:

-   Method A: Silica gel column chromatography eluting with 0-5% MeOH in    DCM or EtOAc.-   Method B: Silica gel column chromatography eluting with 0-90% EtOAc    in cyclohexanes.

MPS1 Example IC50 No Name/Structure Data (μM) 145N-(4-(1,5-dimethyl-1H-pyrazol- 4-yl)-2-methoxyphenyl)-8-(2-oxa-6-azaspiro[3.4]octan-6- yl)pyrido[3,4-d]pyrimidin-2- amine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.15 (d, J = 0.9 Hz, 1H), 8.56 (s, 1H),7.86-7.76 (m, 2H), 7.61 (s, 1H), 7.07 (d, J = 1.9 Hz, 1H), 7.02 (dd, J =8.1, 1.8 Hz, 1H), 6.90 (d, J = 5.5 Hz, 1H), 4.49 (s, 4H), 4.12 (s, 2H),3.88 (s, 3H), 3.80 (s, 3H), 3.73 (t, J = 6.9 Hz, 2H), 2.42 (s, 3H), 2.14(t, J = 6.9 Hz, 2H). HRMS (ESI) MS m/z calcd for C₂₅H₂₈N₇O₂ [M + H]⁺458.2299, found 458.229. Using 2-oxa-6-azaspiro[3.4]octane at 130° C.for 7 hours and purification method A. 0.002 146 N²-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-2- methoxyphenyl)-N⁸-((3- methyloxetan-3-yl)methyl)pyrido(3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.15 (s, 1H), 8.47 (s, 1H), 7.92 (d, J =8.2 Hz, 1H), 7.80 (d, J = 5.5 Hz, 1H), 7.59 (s, 1H), 7.03 (d, J = 1.9Hz, 1H), 6.97 (dd, J = 8.2, 1.9 Hz, 1H), 6.90 (d, J = 5.6 Hz, 1H), 4.89(t, J = 5.3 Hz, 1H), 4.35 (br s, J = 5.7 Hz, 1H), 4.15 (br. s, 2H), 3.88(br. s, 4H), 3.80 (s, 3H), 3.41 (d, J = 5.3 Hz, 2H), 2.40 (s, 3H), 1.23(s, 3H). HRMS (ESI) MS m/z calcd for C₂₄H₂₈N₇O₂ [M + H]⁺ 446.2299, found446.2284. Using (3-methyloxetan-3-yl)methanamine at 130° C. for 8 hoursand purification method A. 0.004 147 N²-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-2- methoxyphenyl)-N⁸-(2- methoxy-2-methylpropyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.19 (s, 1H), 8.59 (s, 1H), 8.18 (d, J =8.2 Hz, 1H), 7.78 (d, J = 5.6 Hz, 1H), 7.61 (s, 1H), 7.08 (d, J = 1.9Hz, 1H), 6.98 (dd, J = 8.2, 1.9 Hz, 1H), 6.88 (d, J = 5.7 Hz, 1H), 6.67(t, J = 5.5 Hz, 1H), 3.92 (s, 3H), 3.80 (s, 3H), 3.56 (d, J = 5.5 Hz,2H), 3.21 (s, 3H), 2.41 (s, 3H), 1.19 (s, 6H). HRMS (ESI) MS m/z calcdfor C₂₄H₃₀N₇O₂ [M + H]⁺ 448.2455, found 448.2447. Using2-methoxy-2-methylpropan-1-amine at 130° C. and purification method B.0.002 148 N²-(4-(1,5-dimethyl-1H- pyrazol-4-yl)-2-methoxyphenyl)-N⁸-((3- methyltetrahydrofuran-3- yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.19 (s, 1H), 8.53 (s, 1H), 8.26 (d, J =8.2 Hz, 1H), 7.78 (d, J = 5.6 Hz, 1H), 7.60 (s, 1H), 7.07 (d, J = 1.9Hz, 1H), 7.00 (dd, J = 8.2, 1.9 Hz, 1H), 6.88 (d, J = 5.7 Hz, 2H), 3.92(s, 3H), 3.86 (td, J = 8.3, 5.6 Hz, 1H), 3.80 (s, 3H), 3.77 (td, J =8.3, 6.9 Hz, 1H), 3.70 (d, J = 8.4 Hz, 1H), 3.57 (qd, J = 13.1, 6.0 Hz,2H), 3.36 (d, J = 8.5 Hz, 1H), 2.41 (s, 3H), 1.92 (ddd, J = 12.2, 8.3,6.8 Hz, 1H), 1.65 (ddd, J = 12.2, 8.1, 5.5 Hz, 1H), 1.15 (s, 3H). HRMS(ESI) MS m/z calcd for C₂₅H₃₀N₇O₂ [M + H]⁺ 460.2455, found 460.2445.Using (3-methyltetrahydrofuran-3- yl)methanamine at 135° C. for 24 hoursand purification method B. 0.003

Example 149N²-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-methyl-N⁸-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine

A solution of N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide(Preparation 56, 35 mg, 0.151 mmol) in THF (1 mL) was treated withsodium hydride (60% w/w, 8 mg, 0.200 mmol) at 0° C. After stirring for20 minutes at room temperature the mixture was cooled to 0° C. and8-chloro-5-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation184, 42 mg, 0.163 mmol) in THF (2 mL) was added. The reaction wasallowed to reach room temperature and stirred for 18 hours. A solutionof aqueous 2M NaOH (1 mL) and MeOH (1 mL) were added and the resultingmixture stirred at room temperature for 1 hour before concentrating invacuo. The residue was partitioned between DCM and water. The aqueouslayer was extracted with DCM and the combined organic layers were driedand concentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with 0 to 75% EtOAc in cyclohexanes to afford theintermediate that was combined with 2,2-dimethylpropan-1-amine (110 μl,0.934 mmol) in N-methyl-2-pyrrolidinone (0.7 mL) and stirred at 130° C.for 13 hours. An additional batch of 2,2-dimethylpropan-1-amine (55 μl,0.47 mmol) was added and the mixture heated to 130° C. for 18 hours. Thereaction was quenched with saturated aqueous NaHCO₃ and extracted withEtOAc. The combined organic layers were washed with water and brine,dried and concentrated in vacuo. The residue was purified by preparativeHPLC (40% to 100% MeOH in H₂O (0.1% formic acid)) to give the titlecompound (20 mg, 50%).

¹H NMR (500 MHz, DMSO-d₆): δ 9.26 (s, 1H), 8.56 (s, 1H), 8.19-8.10 (m,2H), 7.88 (d, J=0.9 Hz, 1H), 7.55 (d, J=1.3 Hz, 1H), 7.28 (d, J=1.9 Hz,1H), 7.14 (dd, J=8.3, 1.8 Hz, 1H), 6.52 (t, J=6.2 Hz, 1H), 3.93 (s, 3H),3.88 (s, 3H), 3.35 (s, 2H), 2.38 (d, J=1.2 Hz, 3H), 0.98 (s, 9H).

HRMS (ESI) MS m/z calcd for C₂₄H₃₀N₇O [M+H]⁺ 432.2506, found 432.2497.

MPS1 IC50 (μM): 0.034

The following Examples were prepared according to Method 5 (Example 54)above using the appropriate chloropyrido[3,4-d]pyrimidine and theappropriate amine as described. The crude reaction residues werepurified as described or according to one of the following methods:

-   Method A: Silica gel column chromatography eluting with 0-10% MeOH    in DCM or EtOAc.-   Method B: Silica gel column chromatography eluting with 0-90% EtOAc    in cyclohexanes.-   Method C: Silica gel column chromatography eluting with 0-40% EtOAc    in cyclohexanes.-   Method D: Silica gel column chromatography eluting with 0-10% MeOH    in EtOAc followed by elution through an SCX-2 cartridge using 1M NH₃    in MeOH.-   Method E: Elution through an SCX-2 column using 1M NH₃ in MeOH.-   Method F: Silica gel column chromatography eluting with 0-10% MeOH    in DCM followed by elution through an SCX-2 cartridge using 1M NH₃    in MeOH followed by silica gel column chromatography eluting with    0-20% MeOH in EtOAc.

MPS1 Example IC50 No Name/Structure Data (μM) 150 N⁸-(2-methoxy-2-methylpropyl)-N²-(2-methoxy- 4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-5-methylpyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.34 (s, 1H), 8.74 (s, 1H), 8.58 (s, 1H),8.44 (d, J = 8.3 Hz, 1H), 7.62 (d, J = 1.2 Hz, 1H), 7.44 (d, J = 1.9 Hz,1H), 7.34 (dd, J = 8.3, 1.9 Hz, 1H), 6.60 (t, J = 5.5 Hz, 1H), 3.98 (s,3H), 3.80 (s, 3H), 3.54 (d, J = 5.5 Hz, 2H), 3.21 (s, 3H), 2.41 (s, 3H),1.19 (s, 6H). HRMS (ESI) MS m/z calcd for C₂₃H₂₉N₈O₂ [M + H]⁺ 449.2408,found 449.2408. Using 8-chloro-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-5- methylpyrido[3,4-d]pyrimidin-2-amine(Preparation 118) and 2-methoxy-2- methylpropan-1-amine at 135° C. for18 hours and purification method A. 0.003 151N²-(2-methoxy-4-(4-methyl-4H- 1,2,4-triazol-3-yl)phenyl)-5-methyl-N⁸-neopentylpyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.33 (s, 1H), 8.74 (s, 1H), 8.58 (s, 1H),8.46 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 1.3 Hz, 1H), 7.43 (d, J = 1.9 Hz,1H), 7.34 (dd, J = 8.3, 1.9 Hz, 1H), 6.61 (br. s, 1H), 3.97 (s, 3H),3.79 (s, 3H), 3.37 (d, J = 6.2 Hz, 2H), 2.40 (d, J = 1.1 Hz, 3H), 0.98(s, 9H). HRMS (ESI) MS m/z calcd for C₂₃H₂₉N₈O [M + H]⁺ 433.2459, found433.2446. Using 8-chloro-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-5- methylpyrido[3,4-d]pyrimidin-2-amine(Preparation 118) and 2,2-dimethylpropan- 1-amine at 135° C. for 18hours and purification method A. 0.002 152N²-(4-(1-ethyl-1H-pyrazol-4-yl)- 2-methoxyphenyl)-N⁸-(2- methoxy-2-methylpropyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.57 (s, 1H), 8.22 (d, J =0.8 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.90 (d, J = 0.8 Hz, 1H), 7.77(d, J = 5.7 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 7.17 (dd, J = 8.2, 1.9Hz, 1H), 6.88 (d, J = 5.7 Hz, 1H), 6.67 (t, J = 5.5 Hz, 1H), 4.17 (q, J= 7.3 Hz, 2H), 3.94 (s, 3H), 3.56 (d, J = 5.6 Hz, 2H), 3.22 (s, 3H),1.43 (t, J = 7.3 Hz, 3H), 1.20 (s, 6H). HRMS (ESI) MS m/z calcd forC₂₄H₃₀N₇O₂ [M + H]⁺ 448.2455, found 448.2461. Using8-chloro-N-(4-(1-ethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)pyrido[3,4-d]pyrimidin- 2-amine (Preparation 119)and 2-methoxy- 2-methylpropan-1-amine at 130° C. for 18 hours andpurification method B. 0.007 153 (3-methoxy-4-(8-(neopentylamino)pyrido[3,4- d]pyrimidin-2- ylamino)phenyl)(3-methoxyazetidin-1- yl)methanone  

¹H NMR (500 MHz, DMSO-d₆): δ 9.24 (s, 1H), 8.69 (s, 1H), 8.41 (d, J =8.3 Hz, 1H), 7.81 (d, J = 5.7 Hz, 1H), 7.30 (d, J = 1.8 Hz, 1H), 7.26(dd, J = 8.3, 1.8 Hz, 1H), 6.89 (d, J = 5.7 Hz, 1H), 6.74 (t, J = 6.2Hz, 1H), 4.51 (br. s, 1H), 4.33-4.21 (br. m, 2H), 4.18 (br. s, 1H), 3.94(s, 3H), 3.86 (br. s, 1H), 3.40 (d, J = 6.4 Hz, 2H), 3.24 (s, 3H), 0.99(s, 9H). HRMS (ESI) MS m/z calcd for C₂₄H₃₁N₆O₃ [M + H]⁺ 451.2452, found451.2458. Using (4-(8-chloropyrido[3,4-d]pyrimidin-2-ylamino)-3-methoxyphenyl)(3- methoxyazetidin-1-yl)methanone (Preparation120) and 2,2- dimethylpropan-1-amine at 130° C. for 18 hours andpurification method B. 0.004 154 N²-(2-methoxy-4-(tetrahydro-2H-pyran-4-yl)phenyl)-N⁸-((3- methyltetrahydrofuran-3-yl)methyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.17 (s, 1H), 8.47 (s, 1H), 8.12 (d, J =8.2 Hz, 1H), 7.76 (d, J = 5.7 Hz, 1H), 6.99 (d, J = 1.9 Hz, 1H), 6.87(d, J = 5.8 Hz, 2H), 6.83 (t, J = 6.1 Hz, 1H), 4.02-3.91 (m, 2H), 3.88(s, 3H), 3.85 (td, J = 8.5, 5.8 Hz, 1H), 3.77 (td, J = 8.3, 6.8 Hz, 1H),3.68 (d, J = 8.5 Hz, 1H), 3.61-3.51 (m, 2H), 3.49-3.42 (m, 2H),3.38-3.30 (m, 1H), 2.84-2.73 (m, 1H), 1.90 (ddd, J = 12.3, 8.3, 6.8 Hz,1H), 1.77-1.69 (m, 4H), 1.65 (ddd, J = 12.2, 8.1, 5.7 Hz, 1H), 1.15 (s,3H). HRMS (ESI) MS m/z calcd for C₂₅H₃₁N₅NaO₃ [M + Na]⁺ 472.2319, found472.2315. Using 8-chloro-N-(2-methoxy-4-(tetrahydro-2H-pyran-4-yl)phenyl)pyrido[3,4- d]pyrimidin-2-amine (Preparation 123)and (3-methyltetrahydrofuran-3-yl)methanamine at 130° C. for 18 hoursand purification method C. 0.007 155 N²-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-5- methyl-N⁸-(3-methyloxetan-3-yl)methyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.32 (s, 1H), 8.68 (br. s, 1H), 8.58 (s,1H), 8.19 (br. d, J = 8.1 Hz, 1H), 7.64 (br. s, 1H), 7.40 (d, J = 1.8Hz, 1H), 7.36 (dd, J = 8.2, 1.8 Hz, 1H), 4.90 (br. t, J = 5.3 Hz, 1H),4.16 (br. d, J = 8.7 Hz, 2H), 3.94 (s, 3H), 3.89 (br. s, 2H), 3.79 (s,3H), 3.42 (d, J = 5.0 Hz, 2H), 2.40 (d, J = 1.1 Hz, 3H), 1.24 (s, 3H).HRMS (ESI) MS m/z calcd for C₂₃H₂₇N₈O₂ [M + H]⁺ 447.2251, found447.2250. Using 8-chloro-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-5- methylpyrido[3,4-d]pyrimidin-2-amine(Preparation 118) and (3-methyloxetan-3- yl)methanamine at 130° C. for36 hours and purification method A 0.004 156N²-(2-methoxy-4-(4-methyl-4H- 1,2,4-triazol-3-yl)phenyl)-5-methyl-N⁸-((3- methyltelrahydrofuran-3- yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.34 (d, J = 0.9 Hz, 1H), 8.67 (s, 1H),8.58 (s, 1H), 8.53 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 1.7 Hz, 1H), 7.43(d, J = 1.9 Hz, 1H), 7.37 (dd, J = 8.3, 1.8 Hz, 1H), 6.88 (br. s, 1H),3.98 (s, 3H), 3.86 (td, J = 8.4, 5.5 Hz, 1H), 3.80 (s, 3H), 3.76 (td, J= 8.4, 7.0 Hz, 1H), 3.72 (d, J = 8.5 Hz, 1H), 3.59 (dd, J = 13.1, 6.5Hz, 1H), 3.52 (dd, J = 13.1, 5.6 Hz, 1H), 3.36 (d, J = 8.5 Hz, 1H), 2.40(s, 3H), 1.93 (ddd, J = 12.3, 8.3, 6.9 Hz, 1H), 1.65 (ddd, J = 12.3,8.1, 5.5 Hz, 1H), 1.15 (s, 3H). HRMS (ESI) MS m/z calcd for C₂₄H₂₉N₈O₂[M + H]⁺ 461.2408, found 461.2411. Using8-chloro-N-(2-methoxy-4-(4-methyl- 4H-1,2,4-triazol-3-yl)phenyl)-5-methylpyrido+3,4-d+pyrimidin-2-amine (Preparation 118) and (3-methyltetrahydrofuran-3-yl)methanamine at 130° C. for 36 hours andpurification method A. 0.005 157 N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-5- methyl-8-(6-oxa-2- azaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-2- amine  

¹H NMR (500 MHz, DMSO-d₆): δ 9.34 (s, 1H), 8.70 (br. s, 1H), 8.58 (s,1H), 8.17 (d, J = 8.2 Hz, 1H), 7.69 (s, 1H), 7.41 (d, J = 1.9 Hz, 1H),7.38 (dd, J = 8.2, 1.9 Hz, 1H), 4.25 (s, 4H), 3.94 (s, 3H), 3.81 (s,2H), 3.79 (s, 3H), 3.71 (t, J = 6.9 Hz, 2H), 2.42 (d, J = 1.1 Hz, 3H),2.14 (t, J = 6.9 Hz, 2H). HRMS (ESI) MS m/z calcd for C₂₄H₂₇N₈O₂ [M +H]⁺ 459.2251, found 459.2247. Using 8-chloro-N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-5- methylpyrido[3,4-d]pyrimidin-2-amine(Preparation 118) and 6-oxa-2- azaspiro[3.4]octane oxalate andtriethylamine at 130° C. for 36 hours and purification method A. 0.006158 N2-(4-(1,2-dimethyl-1H- imidazol-5-yl)-2- methoxyphenyl)-N8-(2-methoxy-2-methylpropyl)-6- methylpyrido[3,4-d]pyrimidine- 2,8-diamine  

¹H NMR (500 MHz, MeOD): δ 9.03 (s, 1H), 8.63 (d, J = 8.5 Hz, 1H), 7.09(d, J = 2.0 Hz, 1H), 7.06 (dd, J = 8.5 and 2.0 Hz, 1H), 6.89 (s, 1H),6.72 (d, J = 1.0 Hz, 1H), 4.02 (s, 3H), 3.65 (s, 2H), 3.63 (s, 3H), 3.35(s, 3H), 2.45 (s, 3H), 2.44 (d, J = 1.0 Hz, 3H), 1.32 (s, 6H). HRMS(ESI) calcd for C₂₆H₃₂N₇O₂ [M + H]⁺ 462.2612, found 462.2605. Using8-chloro-N-(4-(1,2-dimethyl-1H- imidazol-5-yl)-2-methoxyphenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine (Preparation 121) and 2-methoxy-2-methylpropylamine at 135° C. for 24 hours and purification method D.0.003 159 N-(2-ethoxy-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-8-(2-oxa-6-azaspiro[3.4]octan-6- yl)pyrido[3,4-d]pyrimidin-2- amine  

¹H NMR (500 MHz, MeOD): δ 9.06 (s, 1H), 7.99-7.97 (m, 2H), 7.84 (app s,1H), 7.80 (d, J = 6.0 Hz, 1H), 7.24-7.22 (m, 2H), 6.89 (d, J = 6.0 Hz,1H), 4.66 (q, J = 7.0 Hz, 4H), 4.29 (br s, 2H), 4.23 (q, J = 7.0 Hz,2H), (s, 3H), 3.86 (t, J = 7.0 Hz, 2H), 2.25 (t, J = 7.0 Hz, 2H), 1.46(t, J = 7.0 Hz, 3H). HRMS (ESI) calcd for C₂₅H₂₈N₇O₂ [M + H]⁺ 458.2299,found 458.2294. Using 8-chloro-N-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin- 2-amine (Preparation 122)and 2-oxa-6- azaspiro[3,4]octane with triethylamine and purificationmethod E. 0.005 160 N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6- methyl-8-(6-oxa-2- azaspiro[3.4]octan-2-yl)pyrido[3,4-d]pyrimidin-2- amine  

¹H NMR (500 Mhz, Acetone-d6): δ 9.11 (s, 1H), 8.62 (d, J = 8.5 Hz, 1H),8.36 (s, 1H), 8.06 (br s, 1H), 7.43 (s, 1H), 7.42 (dd, J = 8.5, 2.0 Hz,1H), 6.83 (s, 1H), 4.46 (br s, 4H), 4.33 (q, J = 7.0 Hz, 2H), 3.93 (s,2H), 3.90 (s, 3H), 3.82 ( t, J = 7.0 Hz, 2H), 2.41 (s, 3H), 2.27 (t, J =7.0 Hz, 2H), 1.54 (t, J = 7.0 Hz, 3H). HRMS (ESI) calcd for C₂₅H₂₉N₈O₂[M + H]⁺ 473.2408, found 473.2409. Using8-chloro-N-(2-ethoxy-4-(4-methyl-4H- 1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine (Preparation 124) and 6-oxa-2-azaspiro[3.4]octane with triethylamine and purification method F. 0.003

Example 161N³-(2-Methoxy-2-methylpropyl)-N²-(2-methoxy-6-(1-methyl-1H-tetrazol-5-yl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine

Method 7

Sodium hydride (3.4 mg, 0.086 mmol) was added to a suspension ofN-(2-methoxy-6-(1-methyl-1H-tetrazol-5-yl)pyridin-3-yl)formamide(Preparation 126, 20 mg, 0.086 mmol) in DMF (815 μL) at 0° C. Afterstirring for 20 minutes at room temperature, the solution was cooled to0° C. andN-(2-methoxy-2-methylpropyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-amine(Preparation 173, 29.2 mg, 0.094 mmol) was added. The reaction was thenstirred for 18 hours at room temperature. 2M aqueous NaOH (0.25 mL) andMeOH (0.25 mL) were added and the reaction mixture was stirred at roomtemperature for 1 hour. The reaction mixture was then concentrated invacuo and the residue partitioned between DCM and water. The aqueouslayer was extracted with DCM and the combined organic layers were washedwith brine, dried (Na₂SO₄) and concentrated in vacuo. The residue waspurified using Biotage silica gel column chromatography eluting withDCM/EtOAc (80/20 to 67/33) followed by elution through an SCX-2 columnusing a mixture of DCM and 1 M ammonia in MeOH to afford the titleproduct as a yellow solid (22 mg, 59%).

¹H NMR (500 MHz, CDCl₃): δ 9.05 (s, 1H), 9.04 (d, J=8.2 Hz, 1H),8.09-8.12 (m, 2H), 7.95 (d, J=5.7 Hz, 1H), 6.78-6.82 (m, 2H), 4.55 (s,3H), 4.18 (s, 3H), 3.66 (d, J=5.2 Hz, 2H), 3.39 (s, 3H), 1.34 (s, 6H).

HRMS (ESI) calcd for C₂₀H₂₅N₁₀O₂ [M+H]⁺, 437.2156, found: 437.2154.

MPS1 IC50 (μM): 0.031

The following Examples were prepared according to Method 7 (Example 161)above using the appropriate pyrido[3,4-d]pyrimidine and the formamide asdescribed in either DMF or THF. The crude reaction residues werepurified as described or according to one of the following methods:

-   Method A: Silica gel column chromatography eluting with 1-10% EtOH    in DCM followed by preparative HPLC eluting with water/MeOH (90/10    to 0/100, containing 0.1% formic acid).-   Method B: Preparative HPLC eluting with water/MeOH (60/40 to 0/100,    containing 0.1% formic acid) followed by Biotage silica gel column    chromatography eluting with 1:1 DCM:EtOAc followed by 3-5% EtOH in    DCM.-   Method C: Preparative HPLC eluting with water/MeOH (60/40 to 0/100,    containing 0.1% formic acid).-   Method D: Silica gel column chromatography eluting with 50-100%    EtOAc in cyclohexanes followed by elution through an SCX column    using 1M NH₃ in MeOH followed by silica gel column chromatography    eluting with 0-10% MeOH in DCM or 0-40% EtOAc in cyclohexanes.-   Method E: Silica gel column chromatography eluting with 0-15% MeOH    in EtOAc followed by elution through an SCX column using 0.7M NH₃ in    MeOH.-   Method F: Silica gel column chromatography eluting with 0-80% EtOAc    in cyclohexanes followed by elution through an SCX column using 0.7M    NH₃ in MeOH.-   Method G: Reverse phase chromatography eluting with 0-50% MeCN in    water followed by silica gel column chromatography eluting with    0-20% EtOAc in cyclohexanes or 0-10% MeOH in DCM.-   Method H: Silica gel column chromatography eluting with 20-60% EtOAc    in cyclohexanes followed by reverse phase chromatography eluting    with 0-75% MeCN in water.-   Method I: Silica gel column chromatography eluting with 20-100%    EtOAc in cyclohexanes

MPS1 Example IC50 No Name/Structure Data (μM) 162N²-(6-(1,2-Dimethyl-1H- imidazol-5-yl)-2- methoxypyridin-3-yl)-N⁸-(2-methoxy-2- methylpropyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, CDCl₃): δ 9.00 (s, 1H), 8.84 (d, J = 8.1Hz, 1H),7.90-7.93 (m, 2H), 7.25 (s, 1H), 7.23 (d, J = 8.1 Hz, 1H), 6.81 (t, J =5.3Hz, 1H), 6.77 (d, J = 5.7Hz, 1H), 4.11 (s, 3H), 3.93 (s, 3H), 3.66(d, J = 5.3 Hz, 2H), 3.38 (s, 3H), 2.48 (s, 3H), 1.34 (s, 3H). HRMS(ESI) calcd for C₂₃H₂₉N₈O₂ [M + H]⁺ 449.2408, found 449.2399. UsingN-(6-(1,2-dimethyl-1H-imidazol-5-yl)- 2-methoxypyridin-3-yl)formamide(Preparation 130) and N-(2-methoxy-2-methylpropyl)-2-(methylsulfonyl)pyrido[3,4- d]pyrimidin-8-amine(Preparation 173) and purification method A 0.003 163 N⁸-(2-Methoxy-2-methylpropyl)-N²-(2-methoxy- 4-(1-methyl-1H-tetrazol-5-yl)phenyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, CDCl₃): δ 9.05 (s, 1H), 8.89 (d, J = 8.4 Hz, 1H), 8.24(s, 1H), 7.94 (d, J = 5.7 Hz, 1H), 7.46 (d, J = 1.9 Hz, 1H), 7.36 (dd, J= 8.4, 1.9 Hz, 1H), 6.84 (t, J = 5.1 Hz, 1H), 6.80 (d, J = 5.7 Hz, 1H),4.25 (s, 3H), 4.07 (s, 3H), 3.68 (d, J = 5.1 Hz, 2H), 3.36 (s, 3H), 1.34(s, 6H). HRMS (ESI) calcd for C₂₁H₂₈N₉O₂ [M + H]⁺ 436.2204, found436.2195. N-(2-methoxy-4-(1-methyl-1H- tetrazol-5-yl)phenyl)formamide(Preparation 131) and N-(2-methoxy-2-methylpropyI)-2-(methylsulfonyl)pyrido[3,4- d]pyrimidin-8-amine(Preparation 173). 0.002 164 N²-(6-(1,3-Dimethyl-1H-pyrazol-4-yl)-2-methoxypyridin- 3-yl)-N⁸-(2-methoxy-2-methylpropyl)pyrido[3,4- d]pyrimidine-2(8-diamine  

¹H NMR (500 MHz, CDCl₃): δ 8.99 (s, 1H), 8.80 (d, J = 8.1 Hz, 1H),7.89-7.91 (m, 2H), 7.75 (s, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.81 (t, J =5.2 Hz, 1H), 6.77 (d, J = 5.7 Hz, 1H), 4.13 (s, 3H), 3.91 (s, 3H), 3.67(d, J = 5.2 Hz, 2H), 3.37 (s, 3H), 2.59 (s, 3H), 1.33 (s, 6H). HRMS(ESI) calcd for C₂₃H₂₉N₈O₂ [M + H]⁺ 449.2408, found 449.2408. UsingN-(6-(1,3-dimethyl-1H-pyrazol-4-yl)- 2-methoxypyridin-3-yl)formamide(Preparation 132) and and N-(2-methoxy- 2-methylpropyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8- amine (Preparation 173) andpurification method B. 0.003 165 N²-(6-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxypyridin- 3-yl)-N⁸-(2-methoxy-2-methylpropyl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, CDCl₃): δ 8.98 (s, 1H), 8.79 (d, J = 8.1 Hz, 1H),7.87-7.90 (m, 2H), 7.80 (s, 1H), 7.14 (d, J = 8.1 Hz, 1H), 6.81 (t, J =5.2 Hz, 1H), 6.75 (d, J = 5.7 Hz, 1H), 4.12 (s, 3H), 3.87 (s, 3H), 3.67(d, J = 5.2 Hz, 2H), 3.38 (s, 3H), 2.68 (s, 3H), 1.34 (s, 6H). HRMS(ESI) calcd for C₂₃H₂₉N₈O₂ [M + H]⁺ 449.2408, found 449.2404. UsingN-(6-(1,5-dimethyl-1H-pyrazol-4-yl)- 2-methoxypyridin-3-yl)formamide(Preparation 133) and N-(2-methoxy-2-methylpropyl)-2-(methylsulfonyl)pyrido[3,4- d]pyrimidin-8-amine(Preparation 173) and purification method C. 0.003 166 N⁸-(2-Methoxy-2-methylpropyl)-N²-(2-methoxy- 6-(1-methyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, CDCl₃): δ 9.05 (s, 1H), 8.94 (d, J = 8.1 Hz, 1H), 8.02(s, 1H), 7.96 (s, 1H), 7.94 (d, J = 5.7 Hz, 1H), 7.34 (d, J = 8.1 Hz,1H), 7.34 (d, J = 8.1 Hz, 1H), 6.80 (m, 2H), 4.47 (s, 3H), 4.16 (s, 3H),3.68 (d, J = 5.2 Hz, 2H), 3.38 (s, 3H), 1.35 (s, 6H). HRMS (ESI) calcdfor C₂₁H₂₈N₉O₂ [M + H]⁺ 436.2204, found 436.2210. UsingN-(2-methoxy-6-(1-methyl-1H-1,2,3- triazol-5-yl)pyridin-3-yl)formamide(Preparation 134) and N-(2-methoxy-2-methylpropyl)-2-(methylsulfonyl)pyrido[3,4- d]pyrimidin-8-amine(Preparation 173) and purification method C. 0.003 167 N⁸-(2-Methoxy-2-methylpropyl)-N²-(2-methoxy- 6-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, CDCl₃): δ 9.01 (s, 1H), 8.88 (d, J = 8.1 Hz, 1H), 8.06(s, 1H), 8.01 (s, 1H), 7.92 (d, J = 5.7 Hz, 1H), 7.60 (d, J = 8.1 Hz,1H), 6.82 (t, J = 5.2 Hz, 1H), 6.78 (d, J = 5.7 Hz, 1H),4.28 (s, 3H),4.18 (s, 3H), 3.67 (d, J = 5.2 Hz, 2H), 3.39 (s, 3H), 1.35 (s, 3H). HRMS(ESI) calcd for C₂₁H₂₈N₉O₂ [M + H]⁺ 436.2204, found 436.2209. UsingN-(2-methoxy-6-(2-methyl-2H-1,2,3- triazol-4-yl)pyridin-3-yl)formamide(Preparation 135) and N-(2-methoxy-2-methylpropyl)-2-(methylsulfonyl)pyrido[3,4- d]pyrimidin-8-amine(Preparation 173) and purification method C. 0.023 168N2-(2-ethyl-4-(1-methyl-1H- pyrazol-4-yl)phenyl)-N8-neopentylpyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, MeOD): δ 9.04 (s, 1H), 7.97 (s, 1H), 7.82 (s, 1H),7.62-7.59 (m, 2H), 7.52 (d, J = 2.0 Hz, 1H), 7.43 (dd, J = 8.5, 2.0 Hz,1H), 6.85 (br d, J = 7.0 Hz, 1H), 3.96 (3H, s), 3.29 (2H, s), 2.75 (q, J= 7.5 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H), 0.97 (9H, s). HRMS (ESI) calcdfor C₂₄H₃₀N₇ [M + H]⁺ 416.2557, found 416.2540. UsingN-(2-ethyl-4-(1-methyl-1H-pyrazol-4- yl)phenyl)formamide (Preparation136) and -(methylsulfonyl)-N-neopentylpyrido[3,4- d]pyrimidin-8-amine(Preparation 47) and purification method D. 0.027 169N2-(4-(1-methyl-1H-pyrazol-4- yl)-2-(trifluoromethoxy)phenyl)-N8-neopentylpyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, MeOD): δ 9.20 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.03(s, 1H), 7.85 (d, J = 0.5 Hz, 1H), 7.72 (d, J = 6.0 Hz, 1H), 7.57 (dd, J= 8.5, 2.0 Hz, 1H), 7.56 (app s, 1H), 6.86 (d, J = 6.0 Hz, 1H), 3.96 (s,3H), 3.37 (s, 2H), 1.04 (s, 9H). HRMS (ESI) calcd for C₂₃H₂₅F₃N₇O [M +H]⁺ 472.2067, found 472.2054. Using N-(4-(1-methyl-1H-pyrazol-4-yl)-2-(trifluoromethoxy)pheny)formamide (Preparation 137) and2-(methylsulfonyl)- N-neopentylpyrido[3,4-d]pyrimidin-8-amine(Preparation 47) and purification method 0.048 170 N2-(2-methoxy-4-(4-morpholinopiperidin-1- yl)phenyl)-N8- neopentylpyrido[3,4-d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, MeOD): δ 9.02 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.66(d, J = 6.0 Hz, 1H), 6.83 (d, J = 6.0 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H),6.61 (dd, J = 8.5, 2.5 Hz, 1H), 3.93 (s, 3H), 3.83-3.76 (m, 6H), 3.38(s, 2H), 2.94-2.84 (m, 4H), 2.77 (dt, J = 12.0, 1.5 Hz, 3H), 2.14 (br d,J = 12.0 Hz, 2H), 1.78-1.70 (m, 2H), 1.07 (s, 9H). HRMS (ESI) calcd forC₂₈H₄₀N₇O₂ [M + H]⁺ 506.3238, found 506.3232. Using N-(2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)formamide (Preparation 138) and2-(methylsulfonyl)- N-neopentylpyrido[3,4-d]pyrimidin-8-amine(Preparation 47) and purification method 0.004 171N2-(2-methoxy-4-(piperidin-1- yl)phenyl)-N8- neopentylpyrido[3,4-d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, MeOD): δ 9.02 (s, 1H), 8.09 (d, J = 9.0 Hz, 1H), 7.65(d, J = 6.0 Hz, 1H), 6.83 (d, J = 6.0 Hz, 1H), 6.75 (d, J = 2.5 Hz, 1H),6.61 (dd, J = 9.0, 2.5 Hz, 1H), 3.92 (s, 3H), 3.37 (s, 2H), 3.15 (app t,J = 5.0 Hz, 4H), 1.77 (app quin, J = 5.0 Hz, 4H), 1.65-1.61 (m, 2H),1.07 (s, 9H). HRMS (ESI) calcd for C₂₄H₃₃N₆O [M + H]⁺ 421.271, found421.2722. Using N-(2-methoxy-4-(piperidin-1- yl)phenyl)formamide(Preparation 139) and 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 47) and purification method F. 0.065172 (1-(3-methoxy-4-((8- (neopentylamino)pyrido[3,4- d]pyrimidin-2-yl)amino)phenyl)piperidin-4- yl)(morpholino)methanone  

¹H NMR (500 MHz, MeOD): δ 9.01 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.66(d, J = 5.5 Hz, 1H), 6.82 (d, J = 5.5 Hz, 1H), 6.75 (d, J = 2.5 Hz, 1H),6.61 (dd, J = 8.5, 2.5 Hz, 1H), 3.93 (s, 3H), 3.73-3.65 (m, 8H),3.63-3.60 (m, 2H), 3.37 (s, 2H), 2.83-2.78 (m, 3H), 1.95-1.90 (m, 2H),1.87-1.84 (m, 2H), 1.07 (s, 9H). HRMS (ESI) calcd for C₂₈H₄₀N₇O₃ [M +H]⁺ 534.3187, found 534.3182. Using N-(2-methoxy-4-(4-(morpholine-4-carbonyl)piperidin-1-yl)phenyl)formamide (Preparation 140) and2-(methylsulfonyl)- N-neopentylpyrido[3,4-d]pyrimidin-8-amine(Preparation 47) and purification method E. 0.012 173N2-(2-methoxy-4-(4- methylpiperazin-1-yl(phenyl)-N8-neopentylpyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, MeOD): 9.01 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.66 (d,J = 6.0 Hz, 1H), 6.81 (d, J = 6.0 Hz, 1H), 6.73 (d, J = 2.5 Hz, 1H),6.58 (dd, J = 8.5, 2.5 Hz, 1H), 3.93 (s, 3H), 3.37 (br s, 2H), 3.22 (appt, J = 5.5 Hz, 4H), 2.67 (app t, J = 5.5 Hz, 4H), 2.38 (s, 3H), 1.07 (s,9H). HRMS (ESI) calcd for C₂₄H₃₄N₇O [M + H]⁺ 436.2819, found 436.2815.Using N-(2-methoxy-4-(4-methylpiperazin- 1-yl)phenyl)formamide(Preparation 141) and 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 47) andpurification method G. 0.004 174 N2-(2-chloro-4- morpholinophenyl)-N8-neopentylpyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, MeOD): δ 9.03 (s, 1H), 7.81 (d, J = 9.5 Hz, 1H), 7.66(d, J = 6.0 Hz, 1H), 7.11 (d, J = 3.0 Hz, 1H), 6.98 (dd, J = 9.5, 3.0Hz, 1H), 6.82 (d, J = 6.0 Hz, 1H), 3.86 (app t, J = 5.0 Hz, 4H), 3.33(s, 2H), 3.17 (app t, J = 5.0 Hz, 4H), 1.01 (s, 9H). HRMS (ESI) calcdfor C₂₂H₂₈ClN₆O [M + H]⁺ 427.2008, found 427.2001. Using N-(2-chloro-4-morpholinophenyl)formamide (Preparation 142) and 2-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 47) andpurification method H. 0.010 175 N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)- N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, MeOD): δ 9.15 (s, 1H), 8.74 (d, J = 8.5 Hz, 1H), 8.57(s, 1H), 7.77 (d, J = 6.0 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H), 7.35 (dd, J= 8.5, 1.5 Hz, 1H), 6.90 (d, J = 6.0 Hz, 1H), 4.07 (s, 3H), 3.87 (s,3H), 3.44 (s, 2H), 1.10 (s, 9H). HRMS (ESI) calcd for C₂₂H₂₇N₈O [M + H]⁺419.2302, found 419.2288. Using N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide (Preparation 221) and2-(methylsulfonyl)-N- neopentylpyrido[3,4-d]pyrimidin-8-amine(Preparation 47) and purification method G. 0.002 176N2-(2-methoxy-4-(4- (methylsulfonyl)piperazin- yl)phenyl)-N8-neopentylpyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, MeOD): 9.02 (s, 1H), 8.14 (d, J = 9.0 Hz, 1H), 7.67 (d,J = 6.0 Hz, 1H), 6.82 (d, J = 6.0 Hz, 1H), 6.77 (d, J = 2.5 Hz, 1H),6.61 (dd, J = 9.0, 2.5 Hz, 1H), 3.94 (s, 3H), 3.42-3.40 (m, 4H), 3.37(s, 2H), 3.29-3.27 (m, 4H), 2.92 (s, 3H), 1.07 (s, 9H). HRMS (ESI) calcdfor C₂₄H₃₄N₇O₃S [M + H]⁺ 500.2438, found 500.2423. UsingN-(2-methoxy-4-(4- yl)phenyl)formamide (Preparation 143) and2-(methylsulfonyl)-N-neopentylpyrido[3,4- d]pyrimidin-8-amine(Preparation 47) and purification method I. 0.003 177N2-(4-(1,2-dimethyl-1H- imidazol-5-yl)-2- methoxyphenyl)-6-methyl-N8-neopentylpyrido[3,4- d]pyrimidine-2,8-diamine  

¹H NMR (500 MHz, MeOD): δ 9.02 (s, 1H), 8.57 (d, J = 8.5 Hz, 1H), 7.09(d, J = 2.0 Hz, 1H), 7.02 (dd, J = 8.5 and 2.0 Hz, 1H), 6.88 (s, 1H),6.70 (d, J = 1.0 Hz, 1H), 4.02 (s, 3H), 3.61 (s, 3H), 3.45 (s, 2H), 2.45(s, 3H), 2.44 (d, J = 1.0 Hz, 3H), 1.09 (s, 9H). HRMS (ESI) calcd forC₂₃H₃₂N₇O [M + H]⁺ 446.2663, found 446.2648. UsingN-(4-(1,2-dimethyl-1H-imidazol-5-yl)- 2-methoxyphenyl)formamide(Preparation 55) and 6-methyl-2-(methysulfonyl)-N- (Preparation 54) andpurification method E. 0.005 178 N-(4-Chloro-2-methoxyphenyl)-8-(2-oxa-6- azaspiro[3.4]octan-6-yl)pyrido[3.4-d]pyrimidin-2- amine  

¹H NMR (500 MHz, CDCl₃): δ 8.99 (s, 1H), 8.22 (d, J = 8.5 Hz, 1H), 7.96(d, J = 5.6 Hz, 1H), 7.66 (s, 1H), 6.99 (dd, J = 8.6, 2.2 Hz, 1H), 6.94(d, J = 2.3 Hz, 1H), 6.81 (d, J = 5.5 Hz, 1H), 4.73 (d, J = 6.4 Hz, 2H),4.69 (d, J = 6.1 Hz, 2H), 4.3 (s, 2H), 4 (t, J = 6.8 Hz, 2H), 3.95 (s,3H), 2.31 (t, J = 6.9 Hz, 2H). HRMS (ESI) calcd for C₂₀H₂₁ClN₅O₂ [M +H]⁺ 398.1378, found 398.1375. Using N-(4-chloro-2-methoxyphenyl)formamide and 6-(2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-yl)-2-oxa-6-azaspiro[3.4]octane (Preparation 220) and purification method F.0.024

Example 179N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine

Method 8

To a solution of6-methyl-2-(methysulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine(Preparation 54, 40 mg, 0.130 mmol) in DMSO (7 mL) was addedN-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide(Preparation 221, 36 mg, 0.156 mmol) and Cs₂CO₃ (85 mg, 0.259 mmol). Thereaction mixture was heated to 100° C. for 18 hours. The reactionmixture was cooled to room temperature and diluted with EtOAc (40 mL)and water (40 mL). The aqueous layer was re-extracted with DCM (40 mL).The combined organic layer was washed with brine (40 mL), dried (MgSO₄)and concentrated in vacuo. The residue was purified by elution throughan SCX-2 column using 1M NH₃ in MeOH to afford the title compound (6.7mg, 48%).

¹H NMR (500 MHz, MeOD): δ 9.05 (s, 1H), 8.75 (d, J=8.5 Hz, 1H), 8.56 (s,1H), 7.42 (d, J=2.0 Hz, 1H), 7.34 (dd, J=8.5, 2.0 Hz, 1H), 6.71 (d,J=1.0 Hz, 1H), 4.07 (s, 3H), 3.87 (s, 3H), 3.48 (s, 2H), 2.44 (app s,3H), 1.10 (s, 9H).

HRMS (ESI) calcd for C₂₃H₂₉N₈O [M+H]⁺ 433.2459, found 433.2447.

MPS1 IC50 (μM): 0.002

The following Examples were prepared according to Method 8 (Example 179)above using the appropriate pyrido[3,4-d]pyrimidine and the formamide oraniline as described. The crude reaction residues were purified asdescribed or according to one of the following methods, and wherenecessary the residue was eluted though an SCX-2 column using 1M or 7MNH₃ in MeOH.

-   Method A: Silica gel column chromatography eluting with 0-10% MeOH    in EtOAc.-   Method B: Silica gel column chromatography eluting with 0-10% MeOH    in DCM.-   Method C: Silica gel column chromatography eluting with 0-10% MeOH    in DCM followed by reverse phase chromatography eluting with    MeOH/water.-   Method D: Preparative TLC eluting with 3% MeOH in EtOAc/DCM 1/1 or    6% MeOH in EtOAc.-   Method E: Elution through an SCX-2 column using 50% MeOH in    chloroform followed by 50% chloroform in 7N NH₃/MeOH.

MPS1 Example IC50 No Name/Structure Data (μM) 180

¹H NMR (500 MHz, acetone-d6): δ 9.11 (s, 1H), 8.81 (d, J = 8.5 Hz, 1H),8.38 (s, 1H), 8.21 (br s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.43 (dd, J =8.5, 2.0 Hz, 1H), 6.81 (br s, 1H), 6.75 (d, J = 0.5 Hz, 1H), 4.11 (s,3H), 3.92 (s, 3H), 3.66 (d, J = 5.0 Hz, 2H), 3.36 (s, 3H), 2.42 (d, J =0.5 Hz, 3H), 1.30 (s, 6H). HRMS (ESI) calcd for C₂₃H₂₉N₈O₂ [M + H]⁺449.2408, found 449.2404. Using N-(2-methoxy-2-methylpropyl)-6-methyl-2-(methylsulfonyl)pyrido[3,4- d]pyrimidin-8-amine (Preparation172) and N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide (Preparation 221) at 120° C. for 18 hours. 0.003181

¹H NMR (500 MHz, MeOD): δ 9.02 (s, 1H), 8.57 (d, J = 8.5 Hz, 1H), 7.17(d, J = 2.0 Hz, 1H), 7.04 (dd, J = 8.5, 2.0 Hz, 1H), 6.86 (s, 1H), 6.70(d, J = 0.5 Hz, 1H), 4.21 (t, J = 5.5 Hz, 2H), 4.01 (s, 3H), 3.52 (t, J= 5.5 Hz, 2H), 3.45 (s, 2H), 3.25 (s, 3H), 2.48 (s, 3H), 2.44 (d, J =0.5 Hz, 3H), 1.09 (s, 9H). HRMS (ESI) calcd for C₂₇H₃₆N₇O₂ [M + H]⁺490.2925, found 490.2921. Using 6-methyl-2-(methysulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 54) andN-(2-methoxy-4-(1- (2-methoxyethyl)-2-methyl-1H-imidazol-5-yl)phenyl)formamide (Preparation 144) at 120° C. for 18 hours andpurification method A. 0.0194 182

¹H NMR (500 MHz, Acetone-d6): δ 9.11 (s, 1H), 8.80 (d, J = 8.5 Hz, 1H),8.37 (s, 1H), 8.21 (br s, 1H), 7.46 (d, J = 2.0 Hz, 1H), 7.40 (dd, J =8.5, 2.0 Hz, 1H), 6.74 (d, J = 0.5 Hz, 1H), 4.35 (q, J = 7.0 Hz, 2H),3.90 (s, 3H), 3.51 (s, 2H), 2.41 (d, J = 0.5 Hz, 3H), 1.55 (t, J = 7.0Hz, 3H), 1.08 (s, 9H). HRMS (ESI) calcd for C₂₄H₃₁N₈O [M + H]⁺ 447.2615,found 447.2629. Using 6-methyl-2-(methysulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 54) andN-(2-ethoxy-4-(4- methyl-4H-1,2,4-triazol-3- yl)phenyl)formamide(Preparation 150) at 120° C. for 18 hours and purification method B.0.003 183

¹H NMR (500 MHz, MeOD): δ 8.92 (s, 1H), 8.18 (d, J = 8.5 Hz, 1H), 6.76(d, J = 2.5 Hz, 1H), 6.64 (s, 1H), 6.60 (dd, J = 8.5, 2.5 Hz, 1H), 3.94(s, 3H), 3.41-3.40 (m, 4H), 3.39 (s, 2H), 3.28-3.26 (m, 4H), 2.91 (s,3H), 2.41 (s, 3H), 1.07 (s, 9H). HRMS (ESI) calcd for C₂₅H₃₆N₇O₃S [M +H]⁺ 514.2595, found 514.2613. Using 6-methyl-2-(methysulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation 54) andN-(2-methoxy-4-(4- (methylsulfonyl)piperazin-1- yl)phenyl)formamide(Preparation 143) at 120° C. for 18 hours and purification method B.0.016 184

¹H NMR (500 MHz, MeOD): δ 9.10 (s, 1H), 8.53 (d, J = 8.5 Hz, 1H), 7.75(d, J = 6.0 Hz, 1H), 7.64 (s, 1H), 7.21 (d, J = 2.0 Hz, 1H), 7.15 (dd, J= 8.5, 2.0 Hz, 1H), 6.89 (d, J = 6.0 Hz, 1H), 4.76 (s, 2H), 4.03 (s,3H), 4.00 (s, 3H), 3.60 (s, 2H), 3.37 (s, 3H), 1.33 (s, 6H). HRMS (ESI)calcd for C₂₄H₃₀N₇O₃ [M + H]⁺ 465.2433, found 465.2426. UsingN-(2-Methoxy-2-methylpropyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8- amine (Preparation 173) and(4-(4- formamido-3-methoxyphenyl)-1-methyl-1H- pyrazol-5-yl)methylformate (Preparation 145) at 120° C. for 18 hours and purificationmethod B. 0.002 185

¹H NMR (500 MHz, MeOD): δ 9.10 (s, 1H), 8.51 (d, J = 8.5 Hz, 1H), 7.75(d, J = 6.0 Hz, 1H), 7.64 (s, 1H), 7.21 (d, J = 2.0 Hz, 1H), 7.15 (dd, J= 8.5, 2.0 Hz, 1H), 6.89 (d, J = 6.0 Hz, 1H), 4.75 (s, 2H), 4.01 (s,3H), 4.00 (s, 3H), 3.96-3.86 (m, 3H), 3.65 (d, J = 13.0 Hz, 1H), 3.58(d, J = 13.0 Hz, 1H), 3.53 (d, J = 8.5 Hz, 3H), 2.06 (m, 1H), 1.83 (m,1H), 1.29 (s, 3H). HRMS (ESI) calcd for C₂₅H₃₀N₇O₃ [M + H]⁺ 476.2405,found 476.2398. Using 2-(methylsulfonyl)-N-((3- methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidin-8-amine (Preparation 174) and(4-(4-formamido-3- methoxyphenyl)-1-methyl-1H-pyrazol-5- yl)methylformate (Preparation 145) and at 120° C. for 18 hours and purificationmethod B. 0.001 186

¹H NMR (500 MHz, MeOD): δ 9.12 (s, 1H), 8.60 (d, J = 8.5 Hz, 1H), 7.77(d, J = 6.0 Hz, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 8.5, 2.0Hz, 1H), 6.90 (d, J = 6.0 Hz, 1H), 6.89 (s, 1H), 4.23 (t, J = 5.5 Hz,2H), 4.02 (s, 3H), 3.60 (s, 2H), 3.53 (t, J = 5.5 Hz, 2H), 3.35 (s, 3H),3.26 (s, 3H), 2.49 (s, 3H), 1.32 (s, 6H). HRMS (ESI) calcd forC₂₆H₃₄N₇O₃ [M + H]⁺ 492.2718, found 492.2714. UsingN-(2-methoxy-2-methylpropyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8- amine (Preparation 173) andN-(2- methoxy-4-(1-(2-methoxyethyl)-2-methyl-1H-imidazol-5-yl)phenyl)formamide (Preparation 144) at 120° C. for 18hours and purification method B. 0.004 187

¹H NMR (500 MHz, MeOD): δ 9.11 (s, 1H), 8.62 (d, J = 8.5 Hz, 1H), 7.77(d, J = 6.0 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.10 (dd, J = 8.5, 2.0Hz, 1H), 6.90 (s, 1H), 6.89 (s, 1H), 4.23 (t, J = 5.5 Hz, 2H), 4.05 (td,J = 8.5, 5.5 Hz, 1H), 4.01 (s, 3H), 3.91-3.87 (m, 3H), 3.66 (d, J = 13.0Hz, 1H), 3.57 (d, J = 13.0 Hz, 1H), 3.53 (t, J = 5.5 Hz, 2H), 3.26 (s,3H), 2.49 (s, 3H), 2.06 (m, 1H), 1.83 (m, 1H), 1.29 (s, 3H). HRMS (ESI)calcd for C₂₇H₃₄N₇O₃ [M + H]⁺ 504.2718, found 504.2717. Using2-(methylsulfonyl)-N-((3- methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidin-8-amine (Preparation 174) andN-(2-methoxy-4-(1- (2-methoxyethyl)-2-methyl-1H-imidazol-5-yl)phenyl)formamide (Preparation 144) at 120° C. for 18 hours andpurification method A. 0.002 188

¹H NMR (500 MHz, MeOD): δ 9.16 (s, 1H), 8.78 (d, J = 8.0 Hz, 1H), 8.56(s, 1H), 7.80 (d, J = 5.5 Hz, 1H), 7.41 (d, J = 1.5 Hz, 1H), 7.38 (dd, J= 8.0, 1.5 Hz, 1H), 6.93 (d, J = 5.5 Hz, 1H), 4.32 (q, J = 7.0 Hz, 2H),3.88 (s, 3H), 3.62 (s, 2H), 3.37 (s, 3H), 1.57 (t, J = 7.0 Hz, 3H), 1.33(s, 6H). HRMS (ESI) calcd for C₂₃H₂₉N₈O₂ [M + H]⁺ 449.2408, found449.2392. Using N-(2-methoxy-2-methylpropyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8- amine (Preparation 173) andN-(2-ethoxy- 4-(4-methyl-4H-1,2,4-triazol-3- yl)phenyl)formamide(Preparation 150) at 120° C. for 18 hours and purification method B.0.002 189

¹H NMR (500 MHz, MeOD): δ 9.15 (s, 1H), 8.81 (d, J = 9.0 Hz, 1H), 8.56(s, 1H), 7.81 (d, J = 6.0 Hz, 1H), 7.41-7.39 (m, 2H), 6.93 (d, J = 6.0Hz, 1H), 4.31 (q, J = 7.0 Hz, 2H), 4.07 (td, J = 8.5, 6.0 Hz, 1H), 3.91(t, J = 9.0 Hz, 2H), 3.87 (s, 3H), 3.69 (d, J = 13.0 Hz, 1H), 3.58 (d, J= 13.0 Hz, 1H), 3.52 (d, J = 9.0 Hz, 1H), 2.07 (m, 1H), 1.84 (m, 1H),1.56 (t, J = 7.0 Hz, 3H), 1.29 (s, 3H). HRMS (ESI) calcd for C₂₄H₂₉N₈O₂[M + H]⁺ 461.2408, found 461.2404. Using 2-(methylsulfonyl)-N-((3-methyltetrahydrofuran-3- yl)methyl)pyrido[3,4-d]pyrimidin-8-amine(Preparation 174) and N-(2-ethoxy-4-(4- methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide (Preparation 150) at 120° C. for 18 hours andpurification method B. 0.001 190

¹H NMR (500 MHz, MeOD): δ 9.09 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H),7.75-7.74 (m, 2H), 7.10-7.07 (m, 2H), 6.89 (d, J = 6.0 Hz, 1H), 4.01 (s,3H), 3.88 (s, 3H), 3.60 (s, 2H), 3.36 (s, 3H), 2.41 (s, 3H), 1.33 (s,6H). HRMS (ESI) calcd for C₂₄H₃₀N₇O₂ [M + H]⁺ 448.2455, found 448.2459.Using N-(2-methoxy-2-methylpropyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8- amine (Preparation 173) andN-(4-(1,3- dimethyl-1H-pyrazol-4-yl)-2- methoxyphenyl)formamide(Preparation 76) at 120° C. for 18 hours and purification method B.0.003 191

¹H NMR (500 MHz, MeOD): δ 9.07 (s, 1H), 8.48 (d, J = 8.5 Hz, 1H), 7.74(d, J = 5.5 Hz, 1H), 7.73 (s, 1H), 7.09 (dd, J = 8.5, 2.0 Hz, 1H), 7.08(s, 1H), 6.88 (d, J = 5.5 Hz, 1H), 4.04 (td, J = 8.0, 5.5, 1H), 3.99 (s,3H), 3.91 (td, J = 8.0, 7.5 Hz, 1H), 3.88 (s, 3H), 3.87 (d, J = 8.5 Hz,1H, 3.60 (q, J = 13.0 Hz, 2H), 3.52 (d, J = 8.5 Hz, 1H), 2.40 (s, 3H),2.05 (m, 1H), 1.82 (m, 1H), 1.28 (s, 3H). HRMS (ESI) calcd forC₂₅H₃₀N₇O₂ [M + H]⁺ 460.2455, found 460.2450. Using2-(methylsulfonyl)-N-((3- methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidin-8-amine (Preparation 174) andN-(4-(1,3-dimethyl- 1H-pyrazol-4-yl)-2- methoxyphenyl)formamide(Preparation 76) at 120° C. for 18 hours and purification method B.0.002 192

¹H NMR (500 MHz, MeOD): δ 8.98 (s, 1H), 8.52 (d, J = 8.0 Hz, 1H), 7.73(s, 1H), 7.08- 7.06 (m, 2H), 6.70 (d, J = 0.5 Hz, 1H), 4.01 (s, 3H),3.88 (s, 3H), 3.64 (s, 2H), 3.36 (s, 3H), 2.44 (d, J = 0.5 Hz, 3H), 2.40(s, 3H), 1.32 (s, 6H). (ESI) calcd for C₂₅H₃₂N₇O₂ [M + H]⁺ 462.2612,found 462.2613. Using N-(2-methoxy-2-methylpropyl)-6-methyl-2-(methylsulfonyl)pyrido[3,4- d]pyrimidin-8-amine (Preparation172) and N-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2- methoxyphenyl)formamide(Preparation 76) at 120° C. for 18 hours and purification method B.0.005 193

¹H NMR (500 MHz, MeOD): δ 9.15 (s, 1H), 8.66 (d, J = 8.0 Hz, 1H), 7.79(d, J = 6.5 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.35 (dd, J = 8.0, 2.0Hz, 1H), 6.92 (d, J = 6.5 Hz, 1H), 4.62 (br m, 1H), 4.38 (m, 1H),4.35-4.28 (m, 3H), 4.04 (s, 3H), 3.61 (s, 2H), 3.37 (s, 3H), 3.35 (s,3H), 1.33 (s, 6H). HRMS (ESI) calcd for C₂₄H₃₁N₆O₄ [M + H]⁺ 467.2401,found 467.2397. Using N-(2-methoxy-2-methylpropyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8- amine (Preparation 173) andN-(2- methoxy-4-(3-methoxyazetidine-1- carbonyl)phenyl)formamide(Preparation 129) at 120° C. for 18 hours and purification method B.0.004 194

¹H NMR (500 MHz, MeOD): δ 9.14 (s, 1H), 8.63 (d, J = 8.5 Hz, 1H), 7.78(d, J = 6.0 Hz, 1H), 7.17 (d, J = 2.0 Hz, 1H), 7.13 (dd, J = 8.5, 2.0Hz, 1H), 6.91 (d, J = 6.0 Hz, 1H), 4.03 (s, 3H), 3.61 (s, 2H), 3.36 (s,3H), 3.13 (s, 6H), 1.32 (s, 6H). HRMS (ESI) calcd for C₂₂H₂₉N₆O₃ [M +H]⁺ 425.2296, found 425.2289. Using N-(2-methoxy-2-methylpropyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8- amine (Preparation 173) and4-formamido- 3-methoxy-N,N-dimethylbenzamide (Preparation 146) at 120°C. for 18 hours and purification method B. 0.011 195

1H NMR (500 MHz, MeOD): δ 9.13 (s, 1H), 8.63 (d, J = 8.5 Hz, 1H), 7.78(d, J = 6.0 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.12 (dd, J = 8.5, 2.0Hz, 1H), 6.91 (d, J = 6.0 Hz, 1H), 4.03 (s, 3H), 3.72 (br s, 4H), 3.60(s, 2H), 3.36 (s, 3H), 2.54 (br s, 4H), 2.38 (s, 3H), 1.32 (s, 6H). HRMS(ESI) calcd for C₂₅H₃₄N₇O₃ [M + H]⁺ 480.2718, found 480.2711. UsingN-(2-methoxy-2-methylpropyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8- amine (Preparation 173) andN-(2- methoxy-4-(4-methylpiperazine-1- carbonyl)phenyl)formamide(Preparation 147) at 120° C. for 18 hours and purification method B.0.008 196

¹H NMR (500 MHz, MeOD): δ 9.06 (s, 1H), 8.79 (d, J = 8.5 Hz, 1H), 8.01(s, 1H), 7.43 (d, J = 1.5 Hz, 1H), 7.40 (dd, J = 8.5, 1.5 Hz, 1H), 6.74(d, J = 1.0 Hz, 1H), 4.08 (s, 3H), 4.07 (s, 3H), 3.66 (s, 2H), 3.37 (s,3H), 2.45 (d, J = 1.0 Hz, 3H), 1.33 (s, 6H). HRMS (ESI) calcd forC₂₃H₂₉N₈O₂ [M + H]⁺ 449.2408, found 449.2391. UsingN-(2-methoxy-2-methylpropyl)-6- methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-amine (Preparation 172) andN-(2-methoxy-4-(1-methyl-1H-1,2,4-triazol- 5-yl)phenyl)formamide(Preparation 127) at 120° C. for 18 hours. 0.020 197

¹H NMR (500 MHz, MeOD): δ 9.01 (s, 1H), 8.41 (d, J = 8.5 Hz, 1H), 8.00(s, 1H), 7.83 (s, 1H), 7.48 (dd, J = 8.5, 2.0 Hz, 1H), 7.45 (m, 1H),6.71 (d, J = 0.5 Hz, 1H), 3.97 (d, J = 4.0 Hz, 1H), 3.95 (s, 3H), 3.62(s, 2H), 3.34 (s, 3H), 2.44 (d, J = 0.5 Hz, 3H), 1.30 (s, 6H). HRMS(ESI) calcd for C₂₄H₂₈F₂N₇O₂ [M + H]⁺ 484.2267, found 484.2246. UsingN-(2-methoxy-2-methylpropyl)-6- methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-amine (Preparation 172) andN-(2-(difluoromethoxy)-4-(1-methyl-1H- pyrazol-4-yl)phenyl)formamide(Preparation 149) at 120° C. for 18 hours and purification method B.0.034 198

¹H NMR (500 MHz, MeOD): δ 9.00 (s, 1H), 8.56 (d, J = 8.5 Hz, 1H), 7.63(s, 1H), 7.21 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 8.5, 2.0 Hz, 1H), 6.71(d, J = 0.5 Hz, 1H), 4.75 (s, 2H), 4.02 (s, 3H), 4.00 (s, 3H), 3.64 (s,2H), 3.37 (s, 3H), 2.44 (d, J = 0.5 Hz, 3H), 1.32 (s, 6H). HRMS (ESI)calcd for C₂₅H₃₂N₇O₃ [M + H]⁺ 478.2561, found 478.2546. UsingN-(2-methoxy-2-methylpropyl)-6- methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-amine (Preparation 172) and(4-(4-formamido-3-methoxyphenyl)-1- methyl-1H-pyrazol-5-yl)methylformate (Preparation 145) at 120° C. for 18 hours and purificationmethod B. 0.009 199

¹H NMR (500 MHz, DMSO-d₆) ): δ 9.52 (s, 1H), 9.27 (s, 1H), 8.10 (d, J =8.5 Hz, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.94 (dd, J = 2.2. 8.5 Hz, 1H),7.91 (d, J = 5.3 Hz, 1H), 6.96 (d, J = 5.5 Hz, 1H), 4.51-4.46 (m, 4H),4.05 (s, 2H), 3.72 (t, J = 6.7 Hz, 2H), 3.29 (s, 3H), 2.14 (t, J = 6.8Hz, 2H). HRMS (ESI) calcd for C₂₀H₂₁ClN₅O₃S [M + H]⁺ 446.1048, found446.1053. Using 6-(2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-yl)-2-oxa-6- azaspiro[3.4]octane (Preparation 220) and2-chloro-4-(methylsulfonyl)aniline and purification method D. 0.025 200

¹H NMR (500 MHz, DMSO-d₆): δ 9.39 (s, 1H), 9.21 (br s, 3H), 9.20 (s,1H), 8.10 (br s, 1H), 7.88 (br s, 2H), 7.85 (d, J = 5.5 Hz, 1H), 6.91(d, J = 5.5 Hz, 1H), 4.46 (d, J = 5.9 Hz, 2H), 4.39 (d, J = 6.0 Hz, 2H),4.02 (s, 2H), 3.69 (t, J = 6.7 Hz, 2H), 2.09 (t, J = 6.9 Hz, 2H). HRMS(ESI) calcd for C₂₃H₂₁ClN₇O [M + H]⁺ 446.1491, found 446.1498. Using6-(2-(methylsulfonyl)pyrido[3,4- d]pyrimidin-8-yl)-2-oxa-6-azaspiro[3.4]octane (Preparation 220) and2-chloro-4-(pyrimidin-5-yl)aniline (WO2012123745 A1) and purificationmethod D. 0.006 201

¹H NMR (500 MHz, DMSO-d₆): δ 9.46 (s, 1H), 9.25 (s, 1H), 8.08 (d, J =1.8 Hz), 8.05- 7.99 (m, 2H), 7.89 (d, J = 5.6 Hz), 6.94 (d, J = 5.5 Hz),4.46 (d, J = 6.0 Hz, 2H), 4.42 (d, J = 6.0 Hz, 2H), 4.03 (s, 2H), 3.71(t, J = 6.9 Hz, 2H), 2.59 (s, 3H), 2.11 (t, J = 7.0 Hz, 2H). HRMS (ESI)calcd for C₂₂H₂₁ClN₇O₂ [M + H]⁺ 450.1440, found 450.1431. Using6-(2-(methylsulfonyl)pyrido[3,4- d]pyrimidin-8-yl)-2-oxa-6-azaspiro[3.4]octane (Preparation 220) and2-chloro-4-(5-methyl-1,3,4-oxadiazol-2- yl)aniline (Preparation 157) andpurification method D. 0.040 202

¹H NMR (500 MHz, DMSO-d₆): δ 9.29 (s, 1H), 9.19 (s, 1H), 7.99 (d, J =8.7 Hz, 1H), 7.77 (d, J = 5.7 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 7.33(dd, J = 8.7, 2.3 Hz, 1H), 7.07 (t, J = 73.3 Hz, 1H), 6.87 (d, J = 5.7Hz, 1H), 3.51 (d, J = 5.6 Hz, 2H), 3.16 (s, 3H), 1.16 (s, 6H). HRMS(ESI) calcd for C₁₉H₂₁ClF₂N₅O₂ [M + H]⁺ 424.1346, found 424.1356. UsingN-(2-methoxy-2-methylpropyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8- amine (Preparation 173) andN-(4-chloro- 2-(difluoromethoxy)phenyl)formamide (Preparation 151) at120° C. for 1 hour and purification method E. 0.070 203

¹H NMR (500 MHz, CDCl₃): δ 8.99 (s, 1H), 8.61 (dd, J = 9.5, 6 Hz, 1H),7.9 (d, J = 5.8 Hz, 1H), 7.61 (s 1H), 7.02-7 (m, 2H), (d, J = 2.3 Hz,1H), 6.76 (d, J = 6 Hz, 2H), 1H), 6.62 (t, J = 72.7 Hz, 1H), 3.63 (d, J= 5.3 Hz, 2H), 3.34 (s, 3H), 1.32 (s, 6H). HRMS (ESI) calcd forC₁₉H₂₁F₃N₅O₂ [M + H]⁺ 408.1642, found 408.1659. UsingN-(2-methoxy-2-methylpropyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8- amine (Preparation 173) andN-(2- (difluoromethoxy)-4-fluorophenyl)formamide (Preparation 152) at120° C. for 1 hour and purification method E. 0.046 204

¹H NMR (500 MHz, CDCl₃): δ 9.00 (s, 1H), 8.66 (d, J = 8.6 Hz, 1H), 7.9(d, J = 5.7 Hz, 1H), 7.62 (s 1H), 7.38 (dd, J = 8.6, 1.9 Hz, 1H), 7.29(d, J = 1.6 Hz, 1H), 6.78 (d, J = 5.8 Hz, 1H), 6.65 (t, J = 73.3 Hz,1H), 3.97 (s, 3H), 3.66 (d, J = 5.2 Hz, 2H), 3.36 (s, 3H), 1.33 (s, 6H).HRMS (ESI) calcd for C₂₃H₂₆F₂N₇O₂ [M + H]⁺ 470.2111, found 470.2118.Using N-(2-methoxy-2-methylpropyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8- amine (Preparation 173) andN-(2- (difluoromethoxy)-4-(1-methyl-1H-pyrazol- 4-yl)phenyl)formamide(Preparation 149) at 120° C. for 1 hour and purification method A. 0.002205

¹H NMR (500 MHz, CDCl₃): δ 9.10 (s, 1H), 8.61 (d, J = 8.7 Hz, 1H), 8.06(d, J = 5.5 Hz, 1H), 1H), 7.95 (s, 1H), 7.74 (d, J = 1.9 Hz, 1H), 7.6(dd, J = 8.7,1.9 Hz, 1H), 6.88 (d, J = 5.5 Hz, 1H), 4.74-4.71 (m, 2H),4.29 (s, 2H), 4.04 (t, J = 6.7 Hz, 2H), 2.34 (t, J = 7 Hz, 2H). HRMS(ESI) calcd for C₂₀H₁₈ClN₆O [M + H]⁺ 393.1225, found 393.1219. Using6-(2-(methylsulfonyl)pyrido[3,4- d]pyrimidin-8-yl)-2-oxa-6-azaspiro[3,4]octane (Preparation 220) and 4-cyano-2-chloroaniline at120° C. for 1 hour and purification method A. 0.087 206

¹H NMR (500 MHz, CDCl₃): δ 9.05(s, 1H), 8.52 (d, J = 8.4 Hz, 1H), 8.03(s, 1H), 8.02 (s, 1H), 7.35 (dd, J = 8.4, 1.7 Hz, 1H), 7.15 (d, J = 1.7Hz, 1H), 6.85 (d, J = 5.5 Hz, 1H), 4.75-4.71 (m, 2H), 4.32 (s, 2H), 4.04(t, J = 6.8 Hz, 2H), 4.01 (s, 3H), 2.33 (t, J = 6.9 Hz, 2H) HRMS (ESI)calcd for C₂₁H₂₁N₆O₂ [M + H]⁺ 389.1721, found 389.1715. Using6-(2-(methylsulfonyl)pyrido[3,4- d]pyrimidin-8-yl)-2-oxa-6-azaspiro[3,4]octane (Preparation 220) andN-(4-cyano-2-methoxyphenyl)formamide (Preparation 148) at 120° C. for 1hour and purification method A. 0.017 207

¹H NMR (500 MHz, CDCl₃): δ 9.03 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.99(d, J = 5.5 Hz, 1H), 7.56 (s, 1H), 7.47 (d, J = 2.4 Hz, 1H), 7.29 (dd, J= 8.9, 2.4 Hz, 1H), 6.83 (d, J = 5.5 Hz, 1H), 4.71 (d, J = 6.2 Hz, 2H),4.68 (d, J = 6.1 Hz, 2H), 4.24 (s, 2H), 3.96 (t, J = 6.9 Hz, 2H), 2.3(t, J = 6.9 Hz, 2H). HRMS (ESI) MS m/z C₁₉H₁₈Cl₂N₅O [M + H]⁺ 398.1378,found 398.1375. Using 6-(2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-yl)-2-oxa-6- azaspiro[3,4]octane (Preparation 220) andN-(2,4-dichlorophenylformamide (Preparation 153) at 120° C. for 1 hourand purification method A. 0.094

Example 208N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-2-amine

8-Chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine(Example 94, 36 mg 0.1 mmole) and pyrimidine-5-boronic acid (18 mg 0.14mmole) with potassium carbonate (50 mg, 0.36 mmole) andtetrakis(triphenylphosphine)palladium(0) (6 mg 0.0005 mmole) weredissolved in DMF (0.8 mL) and placed under argon and the mixture washeated under microwave irradiation at 150° C. for 30 minutes. Thereaction was diluted with ethyl acetate (20 mL) and washed with water (7mL). The aqueous layer was backwashed with ethyl acetate (10 mL). Thecombined organic layers were washed with water (2×10 mL) and with brine,then dried and concentrated in vacuo. The residue was purified usingpreparative TLC eluting with 2:1 ethyl acetate:ethanol followed byrecrystallization from EtOAc to afford the title compound (12 mg, 33%).

¹H NMR (500 MHz, CDCl₃): δ 9.65 (s, 2H), 9.38 (s, 1H), 9.24 (s, 1H),8.65 (d, J=5.04 Hz, 1H), 8.52 (d, J=8.51 Hz, 1H), 8.19 (br s, 1H), 7.78(d, J=0.95 Hz, 1H), 7.64 (s, 1H), 7.62 (d, J=5.04 Hz, 1H), 7.12 (dd,J=1.89, 8.51 Hz, 1H), 7.03 (d, J=1.89 Hz, 1H), 4.00 (s, 3H), 3.98 (s,3H).

HRMS (ESI) calcd for C₂₂H₁₃N₈O [M+H]⁺ 411.1676, found 411.1688.

MPS1 IC50 (μM): 0.200

Example 209N-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-2-aminepyridin-4-ylboronate

The title compound was prepared according to the method described forExample 208 using8-Chloro-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine(Example 94) and pyridine-4-boronic acid for 30 minutes at each of 100°C., 110° C., 120° C. and 130° C.

¹H NMR (500 MHz, CDCl₃): δ 9.22 (s, 1H), 8.84 (d, J=5.99 Hz, 2H), 8.63(d, J=5.36 Hz, 1H), 8.19 (d, J=6.31 Hz, 2H), 7.76 (d, J=0.63 Hz, 1H),7.64 (s, 1H), 7.61 (d, J=5.36 Hz, 1H), 7.03 (dd, 1.89, 6.31 Hz, 1H),7.02 (s, 1H), 4.00 (s, 3H), 3.98 (s, 3H).

HRMS (ESI) calcd for C₂₃H₂₀N₇O [M+H]⁺ 410.1724, found 410.1722.

MPS1 IC50 (μM): 0.007

PREPARATION METHODS Preparation 12-(4-(3-Chloroisoquinolin-5-yl)-1H-pyrazol-1-yl)-N,N-dimethylethanamine

A mixture of 3-chloro-5-(1H-pyrazol-4-yl)isoquinoline (Preparation 3, 28mg, 0.122 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (35.1 mg,0.244 mmol) and K₂CO₃ (50.5 mg, 0.366 mmol) in DMF (4 mL) was stirred at190° C. under microwave irradiation for 90 minutes. The reaction mixturewas diluted with EtOAc, purified by SCX-2 column eluting with 2MNH₃/MeOH and concentrated in vacuo to afford the title compound as ayellow oil that was used in the next step without further purification.

Preparation 23-Chloro-5-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)isoquinoline

To a solution of 3-chloro-5-(1H-pyrazol-4-yl)isoquinoline (Preparation3, 10 mg, 0.42 mmol) in DMF (3 mL) was added NaH (60%, 28 mg, 0.122mmol). After stirring at room temperature for 15 minutes,1-bromo-2-methoxyethane (25.4 mg, 0.183 mmol) was added and the reactionmixture was stirred at 80° C. for 60 minutes. The reaction was dilutedwith brine and extracted with EtOAc, the organic layers were dried withNa₂SO₄ and concentrated in vacuo to afford the title compound that wasused in the next step without further purification (15 mg).

LCMS (ESI) Rt=2.37 minutes MS m/z 288 [M+H]⁺

Preparation 3 3-Chloro-5-(1H-pyrazol-4-yl)isoquinoline

Method 9

A suspension of 5-bromo-3-chloroisoquinoline (522 mg, 2.15 mmol),tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate(697 mg, 2.37 mmol), Pd(dppf)Cl₂.DCM (182 mg, 0.22 mmol) and Na₂CO₃ (2M,2.2 mL, 4.30 mmol) in DME (10 mL) was stirred at 130° C. under microwaveirradiation for 120 minutes. The reaction mixture was filtered andconcentrated in vacuo. The residue was purified using Biotage silica gelcolumn chromatography eluting with between 20-30% EtOAc in cyclohexaneto afford the title compound as a yellow solid (182 mg, 37%).

¹H NMR (500 MHz, MeOD): δ 9.15 (d, J=0.9 Hz, 1H), 8.09 (dt, J=8.4, 1.1Hz, 1H), 8.04 (s, broad, 1H), 8.01 (t, J=0.9 Hz, 1H), 7.87 (s, broad,1H), 7.84 (dd, J=7.1, 1.2 Hz, 1H), 7.72 (dd, J=8.3, 7.2 Hz, 1H).

LCMS (ESI) Rt=2.17 minutes MS m/z 230 [M+H]⁺

Preparation 4 3-Chloro-5-(1-methyl-1H-imidazol-5-yl)isoquinoline

Method 10

A suspension of3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline(Preparation 16 40 mg, 0.14 mmol), 5-iodo-1-methyl-1H-imidazole (43 mg,0.21 mmol), Pd(PPh₃)₄ (16 mg, 0.014 mmol), CsF (63 mg, 0.41 mmol) inDME/MeOH (3/1 mL) was stirred at 150° C. under microwave irradiation for60 minutes. The reaction mixture was filtered and concentrated in vacuo.The residue was purified using Biotage silica gel column chromatographyeluting with 0-4% MeOH in EtOAc to afford the title compound (12 mg,36%).

¹H NMR (500 MHz, CDCl₃): δ 9.17 (d, J=0.9 Hz, 1H), 8.17-8.03 (m, 1H),7.80-7.67 (m, 3H), 7.61 (t, J=0.9 Hz, 1H), 7.22 (d, J=1.2 Hz, 1H), 3.49(s, 3H).

LCMS (ESI) Rt=0.90 minutes MS m/z 244 [M+H]⁺

The following Preparations were prepared according to Methods 9 or 10(Preparations 3 or 4) above using the appropriate chloroisoquinoline andthe appropriate cross-coupling partner as described.

The Preparations were purified according to the methods described or asdescribed below:

-   Method A: Biotage silica gel column chromatography eluting with    30-35% EtOAc in cyclohexane.-   Method B: Biotage silica gel column chromatography eluting with 50%    EtOAc in cyclohexane.

Preparation No Name/Structure Data 5

¹H NMR (500 MHz, CDCl₃): δ 9.07 (d, J = 0.9 Hz, 1H), 7.94 (t, J = 0.9Hz, 1H), 7.90 (dt, J = 8.2, 1.1 Hz, 1H), 7.74 (d, J = 0.8 Hz, 1H),7.69-7.64 (m, 2H), 7.64-7.58 (m, 1H), 4.42-4.18 (m, 3H), 3.00-2.84 (m,2H), 2.28-2.20 (m, 2H), 2.08-1.97 (m, 2H), 1.52 (s, 9H). LCMS (ESI) Rt =2.83 minutes MS m/z 413 [M + H]⁺ Using tert-butyl4-(4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate in Method 9. 6

¹H NMR (500 MHz, CDCl₃): δ 9.17 (d, J = 0.8 Hz, 1H), 8.07 (dt, J = 8.3,1.1 Hz, 1H), 7.70 (dd, J = 8.3, 7.0 Hz, 1H), 7.59 (dd, J = 7.0, 1.2 Hz,1H), 7.45 (t, J = 0.9 Hz, 1H), 2.30 (s, 3H), 2.13 (s, 3H). LCMS (ESI) Rt= 2.42 minutes MS m/z 259 [M + H]⁺ Using3,5-dimethyl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)isoxazolein Method 9 at 110° C. for 90 minutes. 7

¹H NMR (500 MHz, CDCl₃): δ 9.10 (d, J = 0.9 Hz, 1H), 8.02-7.97 (m, 1H),7.97- 7.89 (m, 1H), 7.74 (d, J = 0.8 Hz, 1H), 7.72- 7.59 (m, 3H), 4.07(s, 3H). LCMS (ESI) Rt = 2.30 minutes MS m/z 244 [M + H]⁺ Using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole inMethod 9 at 110° C. for 120 minutes. 8

¹H NMR (500 MHz, CDCl₃): δ 9.10 (d, J = 0.8 Hz, 1H), 8.00 (t, J = 0.9Hz, 1H), 7.92 (dt, J = 8.2, 1.1 Hz, 1H), 7.76 (d, J = 0.8 Hz, 1H),7.72-7.66 (m, 2H), 7.61 (dd, J = 8.2, 7.1 Hz, 1H), 4.64 (hept, J = 6.7Hz, 1H), 1.64 (d, J = 6.7 Hz, 6H). LCMS (ESI) Rt = 2.56 minutes MS m/z272 [M + H]⁺ Using 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Method 9 at 110° C. for 60minutes. 9

¹H NMR (500 MHz, CDCl₃): δ 9.10 (d, J = 0.8 Hz, 1H), 7.95 (ddd, J = 7.8,1.5, 0.9 Hz, 1H), 7.70 (t, J = 0.9 Hz, 1H), 7.66-7.57 (m, 2H), 7.43 (s,1H), 3.98 (s, 3H), 2.17 (s, 3H). LCMS (ESI) Rt = 2.39 minutes MS m/z 258[M + H]⁺ Using 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Method 9 at 130° C. for 60minutes. 10

¹H NMR (500 MHz, CDCl₃): δ 9.17 (d, J = 0.9 Hz, 1H), 8.16-8.09 (m, 1H),7.72 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H), 7.54(t, J = 1.0 Hz, 1H), 6.43 (d, J = 1.9 Hz, 1H), 3.71 (s, 3H). LCMS (ESI)Rt = 2.34 minutes MS m/z 244 [M + H]⁺ Using 5-bromo-3-chloroisoquinolineand 1- methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Method 9 and purification method A. 11

¹H NMR (500 MHz, CDCl₃): δ 9.10 (d, J = 0.9 Hz, 1H), 8.59 (t, J = 0.9Hz, 1H), 8.01- 7.90 (m, 2H), 7.64 (dd, J = 8.2, 7.2 Hz, 1H), 7.53 (d, J= 2.2 Hz, 1H), 6.58 (d, J = 2.2 Hz, 1H), 4.07 (s, 3H). LCMS (ESI) Rt =2.38 minutes MS m/z 244 [M + H]⁺ Using 3-iodo-1-methyl-1H-pyrazole inMethod 10 and purification method A. 12

¹H NMR (500 MHz, CDCl₃): δ 9.10 (d, J = 0.8 Hz, 1H), 7.96 (dt, J = 8.2,1.1 Hz, 1H), 7.72 (t, J = 0.9 Hz, 1H), 7.64 (dd, J = 8.2, 7.1 Hz, 1H),7.57 (dd, J = 7.1, 1.3 Hz, 1H), 7.55 (s, 1H), 3.94 (s, 3H), 2.20 (s,3H). LCMS (ESI) Rt = 2.38 minutes MS m/z 258 [M + H]⁺ Using5-bromo-3-chloroisoquinoline and1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Method 9 and purification method A. 13

¹H NMR (500 MHz, CDCl₃) δ 9.39 (s, 1H), 9.21 (d, J = 0.9 Hz, 1H), 8.92(s, 2H), 8.14 (dt, J = 8.2, 1.2 Hz, 1H), 7.79-7.70 (m, 2H), 7.68-7.57(m, 1H). LCMS (ESI) Rt = 2.03 minutes MS m/z 242 [M + H]⁺ Using5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrimidine in Method 9at 110° C. for 60 minutes. 14

¹H NMR (500 MHz, CDCl₃): δ 9.14 (d, J = 0.9 Hz, 1H), 8.81-8.68 (m, 2H),8.10- 7.99 (m, 1H), 7.80 (ddd, J = 7.7, 2.3, 1.7 Hz, 1H), 7.75-7.62 (m,3H), 7.49 (ddd, J = 7.8, 4.8, 0.9 Hz, 1H). LCMS (ESI) Rt = 2.04 minutesMS m/z 241 [M + H]⁺ Using pyridin-3-ylboronic acid in Method 9 at 110°C. for 60 minutes. 15

¹H NMR (500 MHz, CDCl₃): δ 9.09 (s, 1H), 8.33 (s, 1H), 7.99-7.90 (m,2H), 7.71- 7.55 (m, 2H), 6.79 (dd, J = 3.4, 0.6 Hz, 1H), 6.62 (dd, J =3.4, 1.8 Hz, 1H). LCMS (ESI) MS m/z 230 [M + H]⁺ HRMS (ESI) MS m/z calcdfor C₁₃H₉ClNO [M + H]⁺ 230.0367, found 230.0343. Using furan-2-ylboronicacid in Method 9 at 105° C. for 1 hour.

Preparation 163-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline

A mixture of 5-bromo-3-chloroisoquinoline (63 mg, 0.41 mmol), KOAc (63mg, 0.41 mmol), Pd(dppf)Cl₂.DCM (22 mg, 0.03 mmol) andbis(pinacolato)diboron (63 mg, 0.41 mmol) in DMF (8 mL) was stirred at100° C. under microwave irradiation for 60 minutes. The reaction mixturewas filtered, diluted with NaCl solution and extracted with EtOAc. Thecrude was purified by Biotage silica gel column chromatography elutingwith 20% EtOAc/cyclohexane to afford the title compound as yellow oil(170 mg, 41%).

¹H NMR (500 MHz, CDCl₃): δ 9.06 (d, J=0.9 Hz, 1H), 8.66-8.64 (m, 1H),8.31 (dd, J=6.9, 1.4 Hz, 1H), 8.15-7.96 (m, 1H), 7.60 (dd, J=8.2, 6.9Hz, 1H), 1.44 (s, 12H).

LCMS (ESI) Rt=3.02 minutes MS m/z 290 [M+H]⁺

Preparation 17 2-methoxy-4-(1-methyl-1H-imidazol-5-yl)aniline

Method 11

A suspension of 5-bromo-1-methyl-1H-imidazole (228 mg, 1.42 mmol),2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (423mg, 1.70 mmol), Pd(PPh₃)₄ (164 mg, 0.142 mmol) and CsF (645 mg, 4.25mmol) in DME/MeOH (9/3 mL) was stirred at 150° C. under microwaveirradiation for 60 minutes. The reaction mixture was filtered andconcentrated in vacuo. The residue was purified using Biotage silica gelcolumn chromatography eluting with between 0-4% MeOH in EtOAc to affordthe title compound (137 mg, 48%).

¹H NMR (500 MHz, CDCl₃): δ 7.56 (s, 1H), 7.02 (s, 1H), 6.81-6.76 (m,3H), 3.95 (s, broad, 2H), 3.88 (s, 3H), 3.64 (s, 3H).

LCMS (ESI) Rt=0.43 minutes MS m/z 204 [M+H]⁺

The following Preparations were prepared according to Method 11(Preparation 17) above using the appropriate aniline and heterocycliccross-coupling partner as described.

The Preparations were purified according to the method described or asdescribed below:

-   Method A: Biotage silica gel column chromatography eluting with 40%    EtOAc in cyclohexane.-   Method B: The reaction mixture was diluted with EtOAc and filtered.    The organic layer was extracted with 2M HCl. The combined aqueous    layers were washed with EtOAc and basified with solid NaHCO₃. The    resulting aqueous solution was extracted with EtOAc, dried with    Na₂SO₄ and concentrated in vacuo to afford the title compound with    no further purification.-   Method C: Method B followed by Biotage silica gel column    chromatography eluting with between 25-40% EtOAc in cyclohexane.-   Method D: Biotage silica gel column chromatography eluting with 1-5%    MeOH in DCM.

Preparation No Name/Structure Data 18

¹H NMR (500 MHz, DMSO-d₆): δ 6.77 (s, 1H), 6.65-6.72 (s, 3H), 4.87 (s,2H), 3.78 (s, 3H), 3.46 (s, 3H), 2.31 (s, 3H). LCMS (ESI) Rt = 0.49minutes MS m/z 218 [M + H]⁺ Using 5-bromo-1,2-dimethyl-1H-imidazole. 19

¹H NMR (500 MHz, CDCl₃): δ 7.70 (s, 1H), 7.52 (s, 1H), 6.92 (dd, J =7.9, 1.8 Hz, 1H), 6.90 (d, J = 1.8 Hz, 1H), 6.73 (d, J = 7.9 Hz, 1H),3.94 (s, 3H), 3.91 (s, 3H), 3.80 (s, broad, 2H). LCMS (ESI) Rt = 0.95minutes MS m/z 204 [M + H]⁺ Using 4-bromo-2-methoxyaniline and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole andpurification method A. 20

¹H NMR (500 MHz, CDCl₃): δ 7.52 (d, J = 1.3 Hz, 1H), 7.26 (d, J = 2.0Hz, 1H), 7.06 (dd, J = 8.2, 2.0 Hz, 1H), 6.99 (d, J = 1.3 Hz, 1H), 6.81(d, J = 8.2 Hz, 1H), 4.05 (s, broad, 2H), 3.61 (s, 3H). LCMS (ESI) Rt =0.79 minutes MS m/z 208 [M + H]⁺ Using 5-iodo-1-methyl-1H-imidazole at140° C. in DME. 21

¹H NMR (500 MHz, CDCl₃): δ 7.66 (s, 1H), 7.50 (s, 1H), 7.37 (d, J = 2.0Hz, 1H), 7.18 (dd, J = 8.2, 2.0 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 4.04(s, 2H), 3.93 (s, 3H). LCMS (ESI) Rt = 1.91 minutes MS m/z 208 [M + H]+Using 4-bromo-2-chloroaniline and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-1H-pyrazole at 100° C.in THF and purification method B. 22

¹H NMR (500 MHz, CDCl₃): δ 6.77 (d, J = 7.8 Hz, 1H), 6.71-6.64 (m, 2H),3.96-3.88 (s, broad, 2H), 3.88 (s, 3H), 2.39 (s, 3H), 2.27 (s, 3H). LCMS(ESI) Rt = 1.48 minutes MS m/z 219 [M + H]⁺ Using4-bromo-2-methoxyaniline and 3,5- dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole at 120° C. for 60 minutes and purificationmethod C. 23

¹H NMR (500 MHz, CDCl₃): δ 2.43 (s, 3H), 3.48 (s, 3H), 4.21 (br s, 2H),6.81 (d, J = 8.2 Hz, 1H), 6.87 (s, 1H), 7.05 (dd, J = 8.2, 2.0 Hz, 1H),7.24 (d, J = 2.0 Hz, 1H). LCMS (ESI) Rt = 0.96 minutes MS m/z 222 [M +H]⁺ Using 5-bromo-1,2-dimethyl-1H-imidazole for 10 minutes at 150° C.and purification method D.

Preparation 24 4-amino-3-methoxy-N,N-dimethylbenzamide

HATU (0.296 g, 0.778 mmol) was added to a solution of4-amino-3-methoxybenzoic acid (0.1 g, 0.598 mmol), DIPEA (0.156 mL,0.897 mmol) and dimethylamine (2M in THF, 0.598 mL, 1.196 mmol) in THF(1.617 ml). The reaction mixture was stirred for 18 hours. The reactionwas partitioned between EtOAc and water, the organic layers were washedwith water, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by Biotage silica gel column chromatography eluting withDCM/EtOAc 60/40 to 40/60 followed by filtration through an SCX-2 columneluting with 2M NH₃/MeOH to afford the title compound as a colourlessoil (69 mg, 59%).

¹H NMR (500 MHz, MeOD): δ 6.95 (d, J=1.8 Hz, 1H), 6.89 (dd, J=8.0, 1.8Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 3.88 (s, 3H), 3.08 (s, 6H).

LCMS (ESI) Rt=0.96 minutes MS m/z 195 [M+H]⁺

Preparation 25 4-amino-3-chloro-N,N-di methylbenzamide

The title compound was prepared according to the method described forPreparation 24 using 4-amino-3-chlorobenzoic acid. Aqueous NaCl solutionwas added and the precipitate was filtered. The filtrate was extractedwith ethyl acetate and the combined organic phases were washed withbrine, dried over anhydrous Na₂SO₄, filtered and evaporated to affordthe title compound (265 mg, 99%).

¹H NMR (500 MHz, MeOD): δ 7.35 (d, J=2.0 Hz, 1H), 7.17 (dd, J=8.3, 2.0Hz, 1H), 6.83 (d, J=8.3 Hz, 1H), 3.07 (s, 6H).

LCMS (ESI) Rt=1.55 minutes MS m/z 199 [M+H]⁺

Preparation 264-amino-N-(1-methylpiperidin-4-yl)-3-(trifluoromethoxy)benzamide

The title compound was prepared according to the method described forPreparation 25 using 4-amino-3-(trifluoromethoxy)benzoic acid and4-amino-1-methylpiperidine.

¹H NMR (500 MHz, DMSO-d₆): δ 8.01 (d, J=7.6 Hz, 1H), 7.66 (s, broad,1H), 7.63 (dd, J=8.4, 2.0 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 3.85-3.74 (m,1H), 3.00-2.92 (m, 2H), 2.69 (s, 3H), 2.32-2.23 (m, 2H), 1.86-1.74 (m,2H), 1.69-1.55 (m, 2H).

LCMS (ESI) Rt=0.95 minutes MS m/z 318 [M+H]⁺

Preparation 27 (4-amino-3-chlorophenyl)(3-methoxyazetidin-1-yl)methanone

The title compound was prepared according to the method described forPreparation 25 using 4-amino-3-chlorobenzoic acid and 3-methoxyazetidinehydrochloride.

¹H NMR (500 MHz, CDCl₃): δ 7.60 (d, J=2.0 Hz, 1H), 7.39 (dd, J=8.4, 1.9Hz, 1H), 6.74 (d, J=8.3 Hz, 1H), 4.45-4.35 (m, 4H), 4.28-4.00 (m, 3H),3.32 (s, 3H).

LCMS (ESI) Rt=1.68 minutes MS m/z 241 [M+H]⁺

Preparation 28(4-amino-3-methoxyphenyl)(3-methoxyazetidin-1-yl)methanone

HATU (2.70 g, 7.10 mmol) was added to a solution of4-amino-3-methoxybenzoic acid (880 mg, 5.26 mmol), 3-methoxyazetidinehydrochloride (0.971 g, 7.86 mmol) and DIPEA (2.85 mL, 16.32 mmol) inTHF (15 mL) at room temperature. THF was removed under reduced pressure,and the residue partitioned between EtOAc and saturated aqueous NaHCO₃.The aqueous layer was extracted with EtOAc and the combined organiclayers were washed with brine, dried and concentrated. The residue waspurified by silica gel column chromatography eluting with 0 to 100%EtOAc in cyclohexane followed by a second chromatography eluting with 0to 4% MeOH in DCM to afford the title compound (728 mg, 59%).

¹H NMR (500 MHz, CDCl₃): δ 7.24 (d, J=1.7 Hz, 1H), 7.06 (dd, J=8.1, 1.8Hz, 1H), 6.66 (d, J=8.0 Hz, 1H), 4.42 (br s, 2H), 4.31-3.99 (m, 5H),3.91 (s, 3H), 3.34 (s, 3H).

Preparation 29(E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A solution of ethoxyethyne (60% w/w in hexanes, 30 mL, 154 mmol) in DCM(230 mL) was cooled at 0° C. and pinacol borane (27 mL, 186 mmol) wasadded followed by Cp₂Zr(H)Cl (1.96 g, 7.60 mmol). The mixture wasallowed to reach room temperature and stirred for 18 hours. The reactionwas filtered through a pad of neutral alumina eluting with 10% EtOAc incyclohexane to afford the title compound (27.66 g, 91%).

¹H NMR (500 MHz, CDCl₃): δ 7.05 (d, J=14.4 Hz, 1H), 4.45 (d, J=14.4 Hz,1H), 3.86 (q, J=7.1 Hz, 2H), 1.30 (t, J=7.1 Hz, 3H), 1.27 (s, 12H).

Preparation 30 Methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate

A solution of 5-bromo-2-(methylthio)pyrimidine-4-carboxylic acid (7.64g, 30.7 mmol) in MeOH (60 mL) was treated with sulfuric acid (2 mL) andboiled for 24 hours. The mixture was poured onto ice water and extractedwith DCM. The DCM phase was washed with saturated aqueous sodiumhydrogen carbonate solution, dried and evaporated to give the titlecompound (6.42 g, 80%).

¹H NMR (500 MHz, CDCl₃): δ 8.72 (s, 1H), 4.01 (s, 3H), 2.58 (s, 3H).

LCMS (ESI) Rt=2.35 minutes 263 [M+H]⁺

Preparation 31 (E)-methyl5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylate

A solution of(E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 29, 4.34 g, 21.91 mmol), methyl5-bromo-2-(methylthio)pyrimidine-4-carboxylate (Preparation 30, 3.81 g,14.48 mmol) and Pd(dppf)Cl₂.DCM (505 mg, 0.618 mmol) was dissolved inTHF (45 mL) and 2M sodium carbonate in water (15 mL) and heated to 65°C. for 18 hours. The mixture was diluted with EtOAc and quenched withbrine. The aqueous layer was extracted with EtOAc three times. Thecombined organic layers were washed with water and brine, dried andconcentrated. The residue was purified by silica gel columnchromatography eluting with 0 to 10% EtOAc in cyclohexane to give thetitle compound (2.30 g, 63%).

¹H NMR (500 MHz, CDCl₃): δ 8.67 (s, 1H), 6.96 (d, J=13.1 Hz, 1H), 6.26(d, J=13.1 Hz, 1H), 4.13-3.81 (m, 5H), 2.60 (s, 3H), 1.37 (t, J=7.0 Hz,3H).

LCMS (ESI) Rt=2.49 minutes MS m/z 255 [M+H]⁺

Preparation 32 2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one

(E)-Methyl 5-(2-ethoxyvinyl)-2-(methylthio)pyrimidine-4-carboxylate(Preparation 31, 2.30 g, 9.04 mmol) was treated with ammonia in methanol7M (45 mL) and heated to 85° C. for 18 hours in a capped vial. Thesolvent was removed under reduced pressure, and the resulting solid wastreated with TsOH monohydrate (175 mg, 0.92 mmol), suspended in toluene(50 mL) and heated to 90° C. for 2 hours. The mixture was concentratedand the residue was purified by silica gel column chromatography elutingwith 0 to 5% MeOH in DCM to give the title compound (1.47 g, 84%).

¹H NMR (500 MHz, DMSO): δ 9.21 (s, 1H), 7.28 (d, J=7.0 Hz, 1H), 6.58 (d,J=7.0 Hz, 1H), 2.60 (s, 3H).

LCMS (ESI) Rt=1.38 minutes MS m/z 194 [M+H]⁺

Preparation 33 8-Chloro-2-(methylthio)pyrido[3,4-d]pyrimidine

A solution of 2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one(Preparation 32, 1.47 g, 7.61 mmol) in POCl₃ (70 mL) was heated to 70°C. for 18 hours. The reaction was concentrated under reduced pressureand partitioned between EtOAc and saturated aqueous NaHCO₃ solution. Theaqueous layer was extracted with EtOAc and the combined organic layerswere washed with water and brine, dried and concentrated. The residuewas purified by silica gel column chromatography eluting with 0 to 20%EtOAc in cyclohexane to give the title compound (1.39 g, 86%).

¹H NMR (500 MHz, CDCl₃): δ 9.24 (s, 1H), 8.43 (d, J=5.4 Hz, 1H), 7.62(d, J=5.4 Hz, 1H), 2.77 (s, 3H).

LCMS (ESI) Rt=2.36 minutes MS m/z 212 [M+H]⁺

Preparation 348-(1-methyl-1H-pyrazol-4-yl)-2-(methylthio)pyrido[3,4-d]pyrimidine

A solution of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine(Preparation 33, 480 mg, 2.268 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(940 mg, 4.52 mmol) and Pd(dppf)Cl₂.DCM (100 mg, 0.122 mmol) wasdissolved in THF (15 mL) and 2M sodium carbonate in water (5 mL) andheated to 65° C. for 18 hours. The mixture was diluted with EtOAc andquenched with brine. The aqueous layer was extracted with EtOAc threetimes. The combined organic layers were washed with water and brine,dried and concentrated. The residue was purified by silica gel columnchromatography eluting with 0 to 4% MeOH in DCM to give the titlecompound (658 mg, quant).

¹H NMR (500 MHz, CDCl₃): δ 9.22 (s, 1H), 8.67 (s, 1H), 8.63-8.56 (m,2H), 7.47 (d, J=5.3 Hz, 1H), 4.05 (s, 3H), 2.78 (s, 3H).

LCMS (ESI) Rt=2.24 minutes MS m/z 258 [M+H]⁺

Preparation 358-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine

A suspension of8-(1-methyl-1H-pyrazol-4-yl)-2-(methylthio)pyrido[3,4-d]pyrimidine(Preparation 34, 0.584 g, 2.27 mmol) in DCM (22 mL) was treated withmCPBA (77% w/w, 1.12 g, 4.98 mmol) at 0° C. and then allowed to reachroom temperature for 18 hours. The mixture was quenched with water andextracted with DCM. The combined organic layers were washed with water,dried and concentrated. The residue was purified by silica gel columnchromatography eluting with 0 to 100% EtOAc in cyclohexane to give thetitle compound (408 mg, 62%).

¹H NMR (500 MHz, DMSO-d₆): δ 10.00 (s, 1H), 8.91 (d, J=5.4 Hz, 1H), 8.81(s, 1H), 8.53 (s, 1H), 7.99 (d, J=5.4 Hz, 1H), 3.99 (s, 3H), 3.59 (s,3H).

LCMS (ESI) Rt=1.60 minutes MS m/z 290 [M+H]⁺

Preparation 36 2-(methylsulfonyl)-8-phenylpyrido[3,4-d]pyrimidine

A solution of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine(Preparation 33, 131 mg, 0.619 mmol) phenylboronic acid (150 mg, 1.230mmol) and Pd(dppf)Cl₂.DCM (25 mg, 0.031 mmol) was dissolved in THF (3mL) and 2M sodium carbonate in water (1 mL) and heated to 60° C. for 18hours. The mixture was diluted with EtOAc and quenched with brine. Theaqueous layer was extracted with EtOAc three times. The combined organiclayers were washed with water and brine, dried and concentrated. Theresidue was purified by silica gel column chromatography eluting with 0to 20% EtOAc in cyclohexane to give the crude sulfide (ca. 134 mg).

A suspension of crude sulfide (134 mg, ca. 0.53 mmol) in DCM (5 mL) wastreated with mCPBA (77% w/w, 260 mg, 1.157 mmol) at 0° C. and thenallowed to reach room temperature for 18 hours. The mixture was quenchedwith water and extracted with DCM. The combined organic layers werewashed with water, dried and concentrated. The residue was purified bysilica gel column chromatography eluting with 0 to 60% EtOAc incyclohexane to give the title compound (78 mg, 44% over two steps).

¹H NMR (500 MHz, DMSO-d₆): δ 10.10 (s, 1H), 9.09 (d, J=5.4 Hz, 1H),8.27-8.16 (m, 3H), 7.65-7.51 (m, 3H), 3.50 (s, 3H).

LCMS (ESI) Rt=1.89 minutes MS m/z 286 [M+H]⁺

Preparation 37 8-cyclopropyl-2-(methylthio)pyrido[3,4-d]pyrimidine

A solution of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine(Preparation 33, 20 mg, 0.094 mmol), cyclopropyl boronic acid (11 mg,0.128 mmol), PCy₃ (3 mg, 10.70 μmol), and Pd(OAc)₂ (1 mg, 4.45 μmol) wasdissolved in toluene/water 6:1 (1 mL) and heated to 95° C. for 18 hours.The mixture was diluted with EtOAc and quenched with brine. The aqueouslayer was extracted with EtOAc three times. The combined organic layerswere washed with water and brine, dried and concentrated. The residuewas purified by silica gel column chromatography eluting with 0 to 20%EtOAc in cyclohexane to give the title compound (13 mg, 62%).

¹H NMR (500 MHz, CDCl₃): δ 9.18 (s, 1H), 8.46 (d, J=5.4 Hz, 1H), 7.37(d, J=5.5 Hz, 1H), 3.46 (tt, J=8.2, 4.8 Hz, 1H), 2.74 (s, 3H), 1.34-1.27(m, 2H), 1.25-1.17 (m, 2H).

LCMS (ESI) Rt=2.65 minutes MS m/z 218 [M+H]⁺

Preparation 38 8-cyclopropyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine

A suspension of 8-cyclopropyl-2-(methylthio)pyrido[3,4-d]pyrimidine(Preparation 37, 127 mg, 0.584 mmol) in DCM (5 mL) was treated withmCPBA (77% w/w, 290 mg, 1.291 mmol) at 0° C. and then allowed to reachroom temperature for 18 hours. The mixture was quenched with water andextracted with DCM. The combined organic layers were washed with water,dried and concentrated on silica gel. The residue was purified by silicagel column chromatography eluting with 0 to 70% EtOAc in cyclohexane togive the title compound (128 mg, 88%).

¹H NMR (500 MHz, DMSO-d₆): δ 9.99 (s, 1H), 8.79 (d, J=5.5 Hz, 1H), 7.94(d, J=5.5 Hz, 1H), 3.56 (s, 3H), 3.49-3.39 (m, 1H), 1.30-1.25 (m, 2H),1.24-1.20 (m, 2H).

LCMS (ESI) Rt=1.49 minutes MS m/z 250 [M+H]⁺

Preparation 39 4-bromo-2-methoxy-5-methylaniline

To a cooled (0° C.) solution of 2-methoxy-5-methylaniline (500 mg, 3.64mmol) in DMF (5 mL) was added slowly, over 10 minutes, a solution ofN-bromosuccinimide (662 mg, 3.72 mmol) in DMF (2.5 mL). The reactionmixture was stirred for 18 hours, whilst slowly warming to roomtemperature. The reaction mixture was diluted with brine (25 mL) andextracted with EtOAc (25 mL). The organic layer was dried (MgSO₄) andconcentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with 0-20% EtOAc in cyclohexane to give the titlecompound (679 mg, 86%). ¹H NMR (500 MHz, CDCl₃): δ 6.93 (s, 1H), 6.62(d, J=0.5 Hz, 1H), 3.83 (s, 3H), 3.73 (br s, 2H), 2.26 (s, 3H).

LCMS (ESI) Rt=1.95 minutes MS m/z 216.297 [M+H]⁺

Preparation 40 2-methoxy-5-methyl-4-(1-methyl-1H-pyrazol-4-yl)aniline

To a solution of 4-bromo-2-methoxy-5-methylaniline (Preparation 39, 350mg, 1.620 mmol) in EtOH (2.5 mL), toluene (2.5 mL) and water (2.5 mL)was added 1-methylpyrazole-4-boronic acid pinacol ester (404 mg, 1.944mmol), sodium carbonate (343 mg, 3.24 mmol) and Pd(PPh₃)₄ (225 mg, 0.194mmol). The reaction mixture was heated to 80° C. for 2.5 hours, undernitrogen. The reaction mixture was cooled to room temperature anddiluted with EtOAc (30 mL), washed with water (30 mL) and brine (30 mL),dried (MgSO₄) and concentrated in vacuo. The residue was purified bysilica gel column chromatography eluting with 0-5% MeOH in DCM to givethe title compound (140 mg, 36%). ¹H NMR (500 MHz, CDCl₃): δ 7.56 (d,J=0.5 Hz, 1H), 7.39 (s, 1H), 6.75 (s, 1H), 6.63 (s, 1H), 3.96 (s, 3H),3.86 (s, 3H), 3.76 (br s, 2H), 2.27 (s, 3H).

LCMS (ESI) Rt=1.13 minutes MS m/z 218.30 [M+H]⁺

Preparation 412-(methylsulfonyl)-8-(pyrrolidin-1-yl)pyrido[3,4-d]pyrimidine

Method 12

A mixture of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (Preparation33, 105 mg, 0.496 mmol) and pyrrolidine (425 μL, 5.08 mmol) inN-methyl-2-pyrrolidinone (2.5 mL) was stirred at 135° C. for 3 hours.The reaction was quenched with saturated aqueous NaHCO₃ and extractedwith EtOAc. The combined organic layers were washed with water andbrine, dried and concentrated to afford the crude sulfide.

A suspension of crude sulfide (ca. 0.49 mmol) in DCM (4 mL) was treatedwith mCPBA (250 mg, 1.113 mmol) at 0° C. and then allowed to reach roomtemperature for 18 hours. An additional portion of mCPBA (77% w/w, 60mg, 0.27 mmol) was added at room temperature and the mixture stirred for2 hours. The mixture was quenched with water and extracted with DCM. Thecombined organic layers were washed with saturated aqueous NaHCO₃,brine, dried and concentrated. The residue was purified by silica gelcolumn chromatography eluting with 0 to 70% EtOAc in cyclohexane to givethe title compound (62 mg, 45% over two steps).

¹H NMR (500 MHz, DMSO-d₆): δ 9.62 (s, 1H), 8.30 (d, J=5.4 Hz, 1H), 7.11(d, J=5.5 Hz, 1H), 3.97 (br s, 4H), 3.45 (s, 3H), 1.98 (s, 4H).

LCMS (ESI) Rt=0.90 minutes MS m/z 279 [M+H]⁺

The following Preparations were prepared according to Method 12 using8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (Preparation 33) and theappropriate amine.

Preparation No Name/Structure Data 42

¹H NMR (500 MHz, DMSO): δ 9.65 (s, 1H), 8.32 (d, J = 5.4 Hz, 1H), 7.16(d, J = 5.3 Hz, 1H), 3.95 (q, J = 6.9 Hz, 4H), 3.44 (s, 3H), 1.30 (t, J= 6.9 Hz, 6H). LCMS (ESI) Rt = 1.48 minutes MS m/z 281 [M + H]⁺ Usingdiethylamine. 43

¹H NMR (500 MHz, DMSO) δ 9.66 (s, 1H), 8.26 (d, J = 5.6 Hz, 1H), 7.64(d, J = 7.4 Hz, 1H), 7.11 (d, J = 5.6 Hz, 1H), 4.53 (h, J = 7.3 Hz, 1H),3.62 (s, 3H), 2.12-1.99 (m, 2H), 1.82-1.72 (m, 2H), 1.73-1.57 (m, 4H).LCMS (ESI) Rt 1.50 minutes MS m/z 293 [M + H]⁺ Using cyclopentylamine.44

¹H NMR (500 MHz, DMSO): δ 9.65 (s, 1H), 8.25 (d, J = 5.6 Hz, 1H), 7.55(d, J = 8.3 Hz, 1H), 7.09 (d, J = 5.6 Hz, 1H), 4.21-4.07 (m, 1H), 3.61(s, 3H), 2.05- 1.91 (m, 2H), 1.85-1.73 (m, 2H), 1.70- 1.62 (m, 1H),1.57-1.44 (m, 2H), 1.42- 1.33 (m, 2H), 1.27-1.13 (m, 1H). LCMS (ESI) Rt= 2.20 minutes MS m/z 307 [M + H]⁺ Using cyclohexylamine. 45

¹H NMR (500 MHz, DMSO): δ 9.67 (s, 1H), 8.26 (d, J = 5.6 Hz, 1H), 7.71(d, J = 8.1 Hz, 1H), 7.13 (d, J = 5.6 Hz, 1H), 4.44-4.33 (m, 1H),3.98-3.89 (m, 2H), 3.62 (s, 3H), 3.52-3.39 (m, 2H), 1.95- 1.85 (m, 2H),1.85-1.71 (m, 2H). LCMS (ESI) Rt = 1.36 minutes MS m/z 309 [M + H]⁺Using aminotetrahydropyrane.

Preparation 46 2-(methylthio)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine

To a solution of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine(Preparation 33, 1 g, 4.72 mmol) in NMP (15 mL) was added neopentylamine(5.5 mL, 4.72 mmol). The reaction mixture was heated to 80° C. for 20hours. The reaction mixture was diluted with saturated aqueous NaHCO₃(50 mL) and EtOAc (2×50 mL). The combined organic layers were washedwith water (50 mL) and brine (50 mL), dried (MgSO₄) and concentrated invacuo. The residue was purified by silica gel column chromatographyeluting with 0-100% EtOAc in cyclohexane give the title compound (915mg, 74%).

¹H NMR (500 MHz, CDCl₃): δ 9.01 (s, 1H), 8.01 (d, J=6.0 Hz, 1H), 6.76(d, J=6.0 Hz, 1H), 6.72 (br s, 1H), 3.46 (d, J=6.0 Hz, 2H), 2.67 (s,3H), 1.06 (s, 9H).

LCMS (ESI) Rt=2.12 minutes MS m/z 263.07 [M+H]⁺

Preparation 472-(methylsulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine

To a cooled (0 C) solution of2-(methylthio)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine (Preparation46, 1.0 g, 4.72 mmol) in DCM (40 mL) was added portionwise mCPBA (2.54g, 11.34 mmol). The reaction mixture was stirred for 18 hours, whilstslowly warming to room temperature. The reaction mixture was quenchedwith water (40 mL) and diluted with DCM (40 mL). The organic layer waswashed with aqueous saturated NaHCO₃ (40 mL), brine (40 mL), dried(MgSO₄) and concentrated in vacuo. The residue was purified by silicagel column chromatography eluting with 0-100% EtOAc in cyclohexane togive the title compound (700 mg, 68%).

¹H NMR (500 MHz, CDCl₃): δ 9.35 (s, 1H), 8.28 (d, J=5.5 Hz, 1H), 6.95(br t, J=6.5 Hz, 1H), 6.92 (d, J=5.5 Hz, 1H), 3.53 (d, J=6.5 Hz, 2H),3.44 (s, 3H), 1.06 (s, 9H).

LCMS (ESI) Rt=2.00 minutes MS m/z 295.05 [M+H]⁺

Preparation 48 4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyaniline

To a solution of 2-methoxy-4-bromoaniline (100 mg, 0.495 mmol) indioxane (2 mL) and water (1 mL) was added boronate ester (143 mg, 0.643mmol), Pd(PPh₃)₄ (57 mg, 0.049 mmol) and sodium carbonate (91 mg, 1.089mmol). The reaction was heated to 120° C. for 30 minutes under microwaveirradiation. The reaction mixture was diluted with EtOAc (30 mL) andwater (30 mL). The aqueous layer was re-extracted with EtOAc (30 mL).The combined organic layer was washed with water (30 mL) and brine (30mL), dried (MgSO₄) and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluting with 0-10% MeOH in EtOAc togive the title compound (35 mg, 33%).

¹H NMR (500 MHz, CDCl₃): δ 7.63 (s, 1H), 6.91 (dd, J=8.0, 2.0 Hz, 1H),6.89 (d, J=2.0 Hz, 1H), 6.85 (app s, 1H), 3.97 (s, 6H), 2.41 (s, 3H).

LCMS (ESI) Rt=1.12 minutes MS m/z 218.20 [M+H]⁺

Preparation 49 Methyl2-(methylthio)-5-prop-1-yn-1-yl)pyrimidine-4-carboxylate

To a solution of methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate(Preparation 30, 1.0 g, 3.80 mmol) in DMF (10 mL) was addedtributylpropynyl tin (1.4 mL, 4.56 mmol) and Pd(PPh₃)₄ (132 mg, 0.114mmol). The reaction mixture was heated to 110° C. under microwaveconditions for 30 minutes. The reaction mixture was diluted with EtOAc(30 mL), washed with aqueous saturated NaHCO₃ (30 mL) and water (30 mL),dried (MgSO₄) and concentrated in vacuo. The residue was purified bysilica gel column chromatography eluting with 50-100% DCM in cyclohexaneto give the title compound (414 mg, 49%).

¹H NMR (500 MHz, CDCl₃): δ 8.67 (s, 1H), 4.00 (s, 3H), 2.61 (s, 3H),2.14 (s, 3H).

LCMS (ESI) Rt=2.42 minutes MS m/z 223.23 [M+H]⁺

Preparation 50 2-(methylthio)-5-(prop-1-yn-1-yl)pyrimidine-4-carboxamide

A solution of methyl2-(methylthio)-5-prop-1-yn-1yl)pyrimidine-4-carboxylate (Preparation 49,410 mg, 1.845 mmol) in NH₃ in MeOH (7M, 12 mL) was heated to 120° C. for18 hours. The reaction mixture was cooled to room temperature andconcentrated in vacuo. The residue was purified by silica gel columnchromatography eluting with 0-5% MeOH in DCM to give the title compound(280 mg, 73%).

¹H NMR (500 MHz, CDCl₃): δ 8.74 (s, 1H), 7.52 (br s, 1H), 5.61 (br s,1H), 2.61 (s, 3H), 2.19 (s, 3H).

LCMS (ESI) Rt=1.87 minutes MS m/z 208.27 [M+H]⁺

Preparation 51 6-methyl-2-(methythio)pyrido[3,4-d]pyrimidin-8(7H)-one

To a solution of2-(methylthio)-5-(prop-1-yn-1yl)pyrimidine-4-carboxamide (Preparation50, 270 mg, 1.303 mmol) in toluene (30 mL) was added pTSA (50 mg, 0.261mmol). The reaction mixture was heated to 90° C. for 18 hours. Thereaction mixture was concentrated in vacuo. The residue was dissolved inNH₃ in MeOH (7M, 10 mL) and heated to 80° C. for 18 hours. The reactionmixture was concentrated in vacuo. The residue was purified by columnchromatography eluting with 0-5% MeOH in DCM to give the title compound(150 mg, 56%).

¹H NMR (500 MHz, CDCl₃): δ 10.52 (br s, 1H), 8.91 (s, 1H), 6.28 (s, 1H),2.72 (s, 3H), 2.45 (s, 3H).

LCMS (ESI) Rt=1.66 minutes MS m/z 208.24 [M+H]⁺

Preparation 52 8-chloro-6-methyl-2-(methythio)pyrido[3,4-d]pyrimidine

A solution of 6-methyl-2-(methythio)pyrido[3,4-d]pyrimidin-8(7H)-one(Preparation 51, 100 mg, 0.483 mmol) in POCl₃ (5 mL) was heated to 70°C. for 1 hour. The reaction mixture was concentrated in vacuo. Theresidue was partitioned between EtOAc (30 mL) and washed with water (30mL), dried (MgSO₄) and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluting with 0-20% EtOAc incyclohexane to give the title compound (28.4 mg, 52%).

¹H NMR (500 MHz, CDCl₃): δ 9.16 (s, 1H), 7.43 (s, 1H), 2.75 (s, 3H),2.71 (s, 3H).

LCMS (ESI) Rt=2.57 minutes MS m/z 226.20 [M+H]⁺

Preparation 536-methyl-2-(methythio)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine

To a solution of 8-chloro-6-methyl-2-(methythio)pyrido[3,4-d]pyrimidine(Preparation 52, 128 mg, 0.567 mmol) in NMP (6 mL) was addedneopentylamine (0.66 mL, 5.67 mmol). The reaction mixture was heated to80° C. for 3 hours. The reaction mixture was diluted with EtOAc (30 mL)and water (30 mL), the organic layer was dried (MgSO₄) and concentratedin vacuo. The residue was purified by silica gel column chromatographyeluting with 0-50% EtOAc in cyclohexane to give the title compound (38mg, 24%).

¹H NMR (500 MHz, CDCl₃): δ 8.93 (s, 1H), 6.70 (br s, 1H), 6.59 (s, 1H),3.48 (br s, 2H), 2.66 (s, 3H), 2.50 (s, 3H), 1.07 (s, 9H).

LCMS (ESI) Rt=2.37 minutes MS m/z 277.31 [M+H]⁺

Preparation 546-methyl-2-(methysulfonyl)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine

To a cooled (0° C.) solution of6-methyl-2-(methythio)-N-neopentylpyrido[3,4-d]pyrimidin-8-amine(Preparation 53, 38 mg, 0.137 mmol) in DCM (2 mL) was added portionwisemCPBA (37 mg, 0.165 mmol). The reaction mixture was stirred for 6 hours,whilst slowly warming to room temperature. The reaction mixture wasquenched with water (40 mL) and diluted with DCM (40 mL). The organiclayer was washed with aqueous saturated NaHCO₃ (40 mL), brine (40 mL),dried (MgSO₄) and concentrated in vacuo. The residue was purified bysilica gel column chromatography eluting with 0-100% EtOAc incyclohexane to give the title compound (12.5 mg, 30%).

¹H NMR (500 MHz, CDCl₃): δ 9.23 (s, 1H), 6.90 (br s, 1H), 6.75 (s, 1H),3.55 (d, J=6.0 Hz, 1H), 3.42 (s, 3H), 2.57 (s, 3H), 1.05 (s, 9H).

LCMS (ESI) Rt=2.44 minutes MS m/z 309.33 [M+H]⁺

Preparation 55N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)formamide

Method 13

A solution of 4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyaniline(Preparation 18, 127 mg, 0.585 mmol) in formic acid (3 mL) was heated toreflux for 1 hour 30 minutes. The solution was concentrated underreduced pressure. The residue was partitioned between saturated aqueousNaHCO₃ and EtOAc. The aqueous layer was extracted with EtOAc and thecombined organic layers washed with water and brine, dried andconcentrated. The residue was purified by silica gel columnchromatography eluting with 0 to 10% MeOH in DCM to give the titlecompound (60 mg, 42%).

¹H NMR (500 MHz, DMSO): δ 9.73 (s, 1H), 8.32 (s, 1H), 8.22 (d, J=8.3 Hz,1H), 7.05 (s, 1H), 6.96 (dd, J=8.2, 1.9 Hz, 1H), 6.86 (s, 1H), 3.89 (s,3H), 3.53 (s, 3H), 2.34 (s, 3H).

LCMS (ESI) Rt=0.83 minutes MS m/z 246 [M+H]⁺

Preparation 56 N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide

The title compound was prepared according to Method 13 (Preparation 55)using 2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline (Preparation 19).The residue was purified by silica gel column chromatography elutingwith 0 to 80% EtOAc in cyclohexane to give the title compound (81 mg,65%).

¹H NMR (500 MHz, DMSO-d₆): δ 9.61 (s, 1H), 8.27 (d, J=2.0 Hz, 1H),8.15-8.05 (m, 2H), 7.85 (s, 1H), 7.22 (d, J=1.8 Hz, 1H), 7.10 (d, J=8.2Hz, 1H), 3.90 (s, 3H), 3.85 (s, 3H).

LCMS (ESI) Rt=1.75 minutes MS m/z 232 [M+H]⁺

Preparation 57 2-(4-iodo-1H-pyrazol-1-yl)ethanol

A solution of 4-iodo-1H-pyrazole (4.50 g, 23.20 mmol) in DMF (45 mL) wastreated with sodium hydride (60% w/w, 1.42 g, 35.5 mmol) at 0° C. andstirred at room temperature. After 1 hour the resulting mixture wastreated with 2-bromoethanol (2.5 mL, 35.2 mmol) at 0° C. The resultingmixture was heated to 65° C. for 3 days. The reaction quenched withbrine/EtOAc and the aqueous layer extracted with EtOAc. The combinedorganic layers were washed with water, brine, dried and concentrated.The residue was purified by silica gel column chromatography elutingwith 0 to 50% EtOAc in cyclohexane to give the title compound (3.55 g,64%).

¹H NMR (500 MHz, CDCl₃): δ 7.55 (s, 1H), 7.52 (s, 1H), 4.32-4.22 (m,2H), 4.04-3.95 (m, 2H), 2.79-2.68 (br m, 1H).

LCMS (ESI) Rt=1.50 minutes MS m/z 238 [M+H]⁺

Preparation 58 2-(4-iodo-1H-pyrazol-1-yl)ethyl 4-methylbenzenesulfonate

2-(4-Iodo-1H-pyrazol-1-yl)ethanol (Preparation 57, 535 mg, 2.248 mmol)in DCM (11 mL) was treated with triethylamine (1.55 mL, 11.14 mmol) at0° C. Tosyl chloride (857 mg, 4.50 mmol) was added at 0° C. and themixture was allowed to warm to room temperature for 18 hours. Theorganic layer was washed with water, HCl 1M and water (twice). Theorganic layers were dried, concentrated and purified by silica gelcolumn chromatography eluting with 0 to 30% EtOAc in cyclohexane to givethe title compound (817 mg, 93%).

¹H NMR (500 MHz, CDCl₃): δ 7.64 (d, J=8.4 Hz, 2H), 7.40 (s, 1H), 7.39(s, 1H), 7.32 (d, J=8.4 Hz, 2H), 4.38-4.34 (m, 4H), 2.47 (s, 3H).

LCMS (ESI) Rt=2.26 minutes MS m/z 393 [M+H]⁺

Preparation 59 1-(2-(4-iodo-1H-pyrazol-1-yl)ethyl)-4-methylpiperazine

A solution of 2-(4-iodo-1H-pyrazol-1-yl)ethyl 4-methylbenzenesulfonate(Preparation 58, 377 mg, 0.961 mmol) in acetonitrile (6 mL) was treatedwith 1-methylpiperazine (1.1 mL, 9.88 mmol). The resulting mixture wasstirred at room temperature for 3 days. The majority of the solvent wasremoved under reduced pressure and the residue partitioned betweensaturated aqueous NaHCO₃ and EtOAc. The aqueous layer was extracted withEtOAc twice and the combined organic layers washed with water, brine,dried and concentrated. The residue was purified by silica gel columnchromatography eluting with 0 to 15% MeOH in DCM to give the titlecompound (208 mg, 68%).

¹H NMR (500 MHz, CDCl₃): δ 7.54 (d, J=0.7 Hz, 1H), 7.50 (d, J=0.7 Hz,1H), 4.25 (t, J=6.6 Hz, 2H), 2.80 (t, J=6.6 Hz, 2H), 2.54-2.46 (br m,8H), 2.32 (s, 3H).

LCMS (ESI) Rt=0.97 minutes MS m/z 321 [M+H]⁺

Preparation 602-methoxy-4-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)aniline

A solution of2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (210mg, 0.843 mmol), 1-(2-(4-iodo-1H-pyrazol-1-yl)ethyl)-4-methylpiperazine(Preparation 59, 206 mg, 0.643 mmol) and Pd(dppf)Cl₂.DCM (52 mg, 0.064mmol) was dissolved in THF (4.5 mL) and 2M sodium carbonate in water(1.5 mL) and heated to 60° C. for 18 hours. The mixture was concentratedunder reduced pressure. The residue was partitioned between water andDCM. The aqueous layer was extracted with DCM three times and thecombined organic layers dried and concentrated. The residue was purifiedby silica gel column chromatography eluting with 0 to 15% MeOH in DCM togive the title compound (72 mg, 35%).

¹H NMR (500 MHz, CDCl₃): δ 7.69 (d, J=0.9 Hz, 1H), 7.61 (d, J=0.8 Hz,1H), 6.93 (dd, J=7.9, 1.8 Hz, 1H), 6.90 (d, J=1.8 Hz, 1H), 6.73 (d,J=7.9 Hz, 1H), 4.27 (t, J=6.8 Hz, 2H), 3.91 (s, 3H), 3.80 (br s, 2H),2.88 (t, J=6.8 Hz, 2H), 2.68-2.40 (m, 8H), 2.32 (s, 3H).

LCMS (ESI) Rt=0.30 minutes MS m/z 316 [M+H]⁺

Preparation 61N-(2-methoxy-4-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)phenyl)formamide

The title compound was prepared according to Method 13 (Preparation 55)using2-methoxy-4-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)aniline(Preparation 60). The residue was purified by silica gel columnchromatography eluting with 0 to 17% MeOH in DCM to give the titlecompound (71 mg, 69%).

¹H NMR (500 MHz, DMSO): δ 9.63 (d, J=2.1 Hz, 1H), 8.28 (d, J=1.9 Hz,1H), 8.17 (s, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.87 (s, 1H), 7.22 (d, J=1.8Hz, 1H), 7.11 (dd, J=8.2, 1.8 Hz, 1H), 4.21 (t, J=6.7 Hz, 2H), 3.91 (s,3H), 2.74 (t, J=6.7 Hz, 2H), 2.48-2.29 (br m, 8H), 2.17 (s, 3H).

LCMS (ESI) Rt=1.16 minutes MS m/z 344 [M+H]⁺

Preparation 62 2-(4-iodo-1H-pyrazol-1-yl)-N,N-dimethylethanamine

2-(4-Iodo-1H-pyrazol-1-yl)ethyl 4-methylbenzenesulfonate (Preparation58) (1.03 g, 2.63 mmol) was treated with dimethylamine in THF (2M, 10mL, 20.00 mmol) and stirred at room temperature for 3 days. Solventswere removed under reduced pressure and the residue partitioned betweenDCM and saturated aqueous NaHCO₃. The aqueous were extracted with DCMand the combined organic layers dried and concentrated. The residue waspurified by silica gel column chromatography eluting with 0 to 10% MeOHin DCM to give the title compound (616 mg, 89%).

¹H NMR (500 MHz, CDCl₃): δ 7.55 (d, J=0.7 Hz, 1H), 7.52 (d, J=0.8 Hz,1H), 4.24 (t, J=6.5 Hz, 2H), 2.74 (t, J=6.5 Hz, 2H), 2.29 (s, 6H).

LCMS (ESI) Rt=0.59 minutes MS m/z 266 [M+H]⁺

Preparation 634-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-2-methoxyaniline

A solution of2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (313mg, 1.256 mmol), 2-(4-iodo-1H-pyrazol-1-yl)-N,N-dimethylethanamine(Preparation 62, 270 mg, 1.019 mmol) and Pd(dppf)Cl₂.DCM (80 mg, 0.098mmol) was dissolved in THF (4.5 mL) and 2M sodium carbonate in water(1.5 mL) and heated to 60° C. for 18 hours. The mixture was concentratedunder reduced pressure. The residue was partitioned between water andDCM and the aqueous layer extracted with DCM three times. The combinedorganic layers were dried and concentrated. The residue was purified bysilica gel column chromatography eluting with 0 to 10% MeOH in DCM togive the title compound (74 mg, 28%).

¹H NMR (500 MHz, CDCl₃): δ 7.70 (s, 1H), 7.62 (s, 1H), 6.93 (dd, J=7.9,1.8 Hz, 1H), 6.90 (d, J=1.8 Hz, 1H), 6.72 (d, J=7.9 Hz, 1H), 4.27 (t,J=6.8 Hz, 2H), 3.91 (s, 3H), 3.79 (br s, 2H), 2.83 (t, J=6.8 Hz, 2H),2.32 (s, 6H).

LCMS (ESI) Rt=0.29 minutes MS m/z 261 [M+H]⁺

Preparation 64N-(4-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide

The title compound was prepared according to Method 13 (Preparation 55)using 4-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-2-methoxyaniline(Preparation 63). The residue was purified by silica gel columnchromatography eluting with 0 to 15% MeOH in DCM.

¹H NMR (500 MHz, DMSO-d₆): δ 9.61 (s, 1H), 8.27 (d, J=1.9 Hz, 1H), 8.17(s, 1H), 8.11 (d, J=8.2 Hz, 1H), 7.86 (d, J=0.9 Hz, 1H), 7.22 (d, J=1.8Hz, 1H), 7.10 (dd, J=8.2, 1.8 Hz, 1H), 4.20 (t, J=6.5 Hz, 2H), 3.90 (s,3H), 2.75-2.63 (m, 2H), 2.20 (s, 6H).

Preparation 651-(2-(tert-butyldiphenylsilyloxy)ethyl)-4-iodo-1H-pyrazole

A solution of 2-(4-iodo-1H-pyrazol-1-yl)ethanol (Preparation 57) (1.01g, 4.24 mmol) in DMF (21 mL) was treated with imidazole (410 mg, 6.03mmol) followed by tert-butylchlorodiphenylsilane (1.321 mL, 5.09 mmol)and the mixture was stirred to room temperature for 18 hours. Themixture was diluted with EtOAc and quenched with brine. The aqueouslayer was extracted with EtOAc three times. The combined organic layerswere washed with water and brine, dried and concentrated. The residuewas purified by silica gel column chromatography eluting with 0 to 10%EtOAc in cyclohexane to give the title compound (2.25 g, quant).

¹H NMR (500 MHz, CDCl₃): δ 7.56 (s, 1H), 7.54-7.50 (m, 5H), 7.47-7.35(m, 6H), 4.26 (t, J=5.2 Hz, 2H), 3.96-3.91 (m, 2H), 1.03 (s, 9H).

LCMS (ESI) Rt=1.98 minutes MS m/z 498 [M+Na]⁺

Preparation 664-(1-(2-(tert-butyldiphenylsilyloxy)ethyl)-1H-pyrazol-4-yl)-2-methoxyaniline

A solution of2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (383mg, 1.537 mmol),1-(2-(tert-butyldiphenylsilyloxy)ethyl)-4-iodo-1H-pyrazole (Preparation65, 554 mg, 1.163 mmol) and Pd(dppf)Cl₂-DCM (90 mg, 0.110 mmol) wasdissolved in THF (6 mL) and 2M sodium carbonate in water (2 mL) andheated to 60° C. for 18 hours. The mixture was diluted with EtOAc andquenched with brine. The aqueous layer was extracted with EtOAc threetimes. The combined organic layers were washed with brine, dried andconcentrated. The residue was purified by silica gel columnchromatography eluting with 0 to 20% EtOAc in cyclohexane to give thetitle compound (141 mg, 26%).

¹H NMR (500 MHz, CDCl₃): δ 7.73 (d, J=0.8 Hz, 1H), 7.71 (d, J=0.8 Hz,1H), 7.61-7.52 (m, 4H), 7.46-7.40 (m, 2H), 7.39-7.34 (m, 4H), 6.94 (dd,J=7.9, 1.8 Hz, 1H), 6.91 (d, J=1.8 Hz, 1H), 6.74 (d, J=7.9 Hz, 1H), 4.30(t, J=5.2 Hz, 2H), 4.01 (t, J=5.2 Hz, 2H)), 3.90 (s, 3H), 3.81 (br s,2H), 1.06 (s, 9H).

LCMS (ESI) Rt=2.83 minutes MS m/z 472 [M+H]⁺

Preparation 67N-(4-(1-(2-(tert-butyldiphenylsilyloxy)ethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide

A solution of4-(1-(2-(tert-butyldiphenylsilyloxy)ethyl)-1H-pyrazol-4-yl)-2-methoxyaniline(Preparation 66, 130 mg, 0.276 mmol) in formic acid (2 mL) was heated toreflux for 3 hours. The solution was concentrated under reduced pressureand azeotroped with toluene twice. The residue was dissolved in MeOH (1mL) and treated with Et₃N (50 μL) at room temperature for 1 hour. Themixture was concentrated under reduced pressure, co-evaporated with DCMtwice to afford the crude formylated aniline.

A solution of crude formylated aniline (ca. 0.27 mmol) in DMF (1.5 mL)was treated with imidazole (30 mg, 0.441 mmol) followed bytert-butylchlorodiphenylsilane (100 μl, 0.386 mmol) and the mixture wasstirred to room temperature for 18 hours. The mixture was diluted withEtOAc and quenched with brine. The aqueous layer was extracted withEtOAc three times. The combined organic layers were washed with waterand brine, dried and concentrated. The residue was purified by silicagel column chromatography eluting with 0 to 40% EtOAc in cyclohexane togive the title compound (126 mg, 91% over two steps).

¹H NMR (500 MHz, CDCl₃): δ 8.48 (d, J=1.8 Hz, 1H), 8.36 (d, J=8.3 Hz,1H), 7.81-7.74 (m, 3H), 7.59-7.52 (m, 5H), 7.45-7.40 (m, 2H), 7.38-7.32(m, 5H), 4.33-4.27 (m, 2H), 4.06-3.99 (m, 2H), 3.93 (s, 3H), 1.04 (s,9H).

LCMS (ESI) Rt=3.08 minutes MS m/z 500 [M+H]⁺

Preparation 688-(cyclopropylmethoxy)-2-(methylthio)pyrido[3,4-d]pyrimidine

A suspension of 2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one(Preparation 32, 502 mg, 2.60 mmol) and silver carbonate (988 mg, 3.58mmol) in CHCl₃ (25 mL) was treated with bromomethyl cyclopropane (310μl, 3.19 mmol) and stirred at room temperature for 18 hours. The mixturewas stirred at reflux for 4 hours and additional bromomethylcyclopropane (310 μl, 3.19 mmol) was added. The reaction was stirred for18 hours at 6° C. Further bromomethyl cyclopropane (310 μl, 3.19 mmol)was added and heated continued for 2 hours. Et₃N was added (6 mL), themixture filtered through celite washing with DCM and the solvent removedunder reduced pressure. The residue was purified by silica gel columnchromatography eluting with 0 to 80% EtOAc in cyclohexane to give thetitle compound (112 mg, 17%).

¹H NMR (500 MHz, CDCl₃): δ 9.14 (s, 1H), 8.07 (d, J=5.6 Hz, 1H), 7.18(d, J=5.6 Hz, 1H), 4.43 (d, J=7.0 Hz, 2H), 2.74 (s, 3H), 1.54-1.43 (m,1H), 0.73-0.61 (m, 2H), 0.54-0.43 (m, 2H).

LCMS (ESI) Rt=2.69 minutes MS m/z 248 [M+H]⁺

Preparation 698-(cyclopropylmethoxy)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine

A suspension of8-(cyclopropylmethoxy)-2-(methylthio)pyrido[3,4-d]pyrimidine(Preparation 68, 110 mg, 0.445 mmol) in DCM (4 mL) was treated withmCPBA (77% w/w, 325 mg, 1.353 mmol) at 0° C. and then allowed to reachroom temperature for 18 hours. The mixture was quenched with water andextracted with DCM. The combined organic layers were washed withsaturated aqueous NaHCO₃, dried and concentrated. The residue waspurified by silica gel column chromatography eluting with 0 to 55% EtOAcin cyclohexane to give the title compound (95 mg, 77%).

¹H NMR (500 MHz, DMSO): δ 9.92 (s, 1H), 8.44 (d, J=5.7 Hz, 1H), 7.72 (d,J=5.7 Hz, 1H), 4.43 (d, J=7.2 Hz, 2H), 3.50 (s, 3H), 1.51-1.32 (m, 1H),0.69-0.57 (m, 2H), 0.49-0.40 (m, 2H).

LCMS (ESI) Rt=1.95 minutes MS m/z 302 [M+Na]⁺

Preparation 70 2-methoxy-6-morpholinopyridin-3-amine

To a solution of 4-(6-methoxy-5-nitropyridin-2-yl)morpholine(Preparation 81, 280 mg, 1.170 mmol) in EtOAc/EtOH (1:1, 10 ml) wasadded palladium on charcoal (10%, 100 mg). The flask was charged withhydrogen and the reaction mixture was stirred at room temperature for 2hours. The reaction mixture was filtered through Celite® andconcentrated in vacuo to give the title compound (245 mg, 99%).

¹H NMR (500 MHz, CDCl₃): δ 6.98 (d, J=8.0 Hz, 1H), 6.09 (d, J=8.0 Hz,1H), 4.05 (br s, 2H), 3.94 (s, 3H), 3.85 (t, J=4.5 Hz, 4H), 3.34 (t,J=4.5 Hz, 4H).

LCMS (ESI) Rt=1.05 minutes MS m/z 210.12 [M+H]⁺

Preparation 71 N-(2-methoxy-6-morpholinopyridin-3-yl)formamide

A solution of 2-methoxy-6-morpholinopyridin-3-amine (Preparation 70, 40mg, 0.191 mmol) in formic acid (3 mL) was heated to reflux for 3 hours.The reaction mixture was concentrated in vacuo. The residue waspartitioned between aqueous saturated NaHCO₃ (40 mL) and EtOAc (40 mL).The aqueous layer was re-extracted with EtOAc (40 mL). The combinedorganic layers were washed with water (40 mL) and brine (40 mL), dried(MgSO₄) and concentrated in vacuo, to give the title compound (40 mg,88%).

LCMS (ESI) Rt=1.84 minutes MS m/z 238.12 [M+H]⁺

Preparation 72 2-methoxy-6-(methysulfonyl)pyridine-3-amine

To a solution of 2-methoxy-6-(methylsulfonyl)-3-nitropyridine(Preparation 83, 290 mg, 1.249 mmol) in EtOAc/EtOH (1:1, 10 mL) wasadded palladium on charcoal (10%, 100 mg). The flask was charged withhydrogen and the reaction mixture was stirred at room temperature for 2hours. The reaction mixture was filtered through Celite® andconcentrated in vacuo to give the title compound (245 mg, 97%).

¹H NMR (500 MHz, CDCl₃): δ 7.51 (d, J=8.0 Hz, 1H), 6.90 (d, J=8.0 Hz,1H), 4.75 (br s, 2H), 4.03 (s, 3H), 3.13 (s, 3H).

LCMS (ESI) Rt=1.52 minutes MS m/z 203.05 [M+H]⁺

Preparation 73 N-(2-methoxy-6-(methylsulfonyl)pyridin-3-yl)formamide

The title compound was prepared according to Method 13 (Preparation 55)using 2-methoxy-6-(methysulfonyl)pyridine-3-amine (Preparation 72) for 3hours. The crude residue was used directly in the next reaction.

LCMS (ESI) Rt=1.26 minutes MS m/z 231.06 [M+H]⁺

Preparation 74N-(2-methoxy-4-(1-methyl-1H-imidazol-5-yl)phenyl)formamide

The title compound was prepared according to Method 13 (Preparation 55)using 2-methoxy-4-(1-methyl-1H-imidazol-5-yl)aniline (Preparation 17).The crude residue was used directly in the next reaction.

¹H NMR (500 MHz, MeOD): δ 8.36 (s, 1H), 8.33 (d, J=8.0 Hz, 1H), 7.69 (s,1H), 7.10 (d, J=2.0 Hz, 1H), 7.04 (dd, J=8.0, 2.0 Hz, 2H), 3.96 (s, 3H),3.74 (s, 3H).

LCMS (ESI) Rt=0.69 minutes MS m/z 232.11 [M+H]⁺

Preparation 75 4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyaniline

A suspension of2-methoxy-4-(4,4,5,5-tetramethy-1,3,2-dioxaborolan-2-yl)aniline (50 mg,0.201 mmol), 4-bromo-1,3-methylpyrazole (35 mg, 0.201 mmol), CsF (91 mg,0.602 mmol) and Pd(PPh₃)₄ (12 mg, 10.04 umol) in DME/MeOH (2:1, 1.5 mL)was heated to 150° C. for 10 minutes, under microwave irradiation. Thereaction mixture was diluted with EtOAc (30 mL) and water (30 mL). Theorganic layer was washed with water (30 mL), brine (30 mL), dried(MgSO₄) and concentrated in vacuo. The residue was purified by silicagel column chromatography eluting with 0-20% MeOH in EtOAc to give thetitle compound (10 mg, 23%).

¹H NMR (500 MHz, CDCl₃): δ 7.38 (s, 1H), 6.92 (d, J=8.0 Hz, 1H),6.85-6.83 (m, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 2.39 (s, 3H).

LCMS (ESI) Rt=1.15 minutes MS m/z 218.14 [M+H]⁺

Preparation 76N-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide

The title compound was prepared according to Method 13 (Preparation 55)using 4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyaniline (Preparation75). The crude residue was used directly in the next reaction.

¹H NMR (500 MHz, MeOD): δ 8.33 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.72 (s,1H), 7.05 (d, J=2.0 Hz, 1H), 6.99 (dd, J=8.5, 2.0 Hz, 1H), 3.95 (s, 3H),3.86 (s, 3H), 2.37 (s, 3H).

LCMS (ESI) Rt=1.92 minutes MS m/z 246.11 [M+H]⁺

Preparation 77N-(4-(1,5-dimethy-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide

The title compound was prepared according to Method 13 (Preparation 55)using 4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyaniline (Preparation48). The crude residue was used directly in the next reaction.

LCMS (ESI) Rt=1.90 minutes MS m/z 246.10 [M+H]⁺

Preparation 78 4-(3-methoxy-4-nitrophenyl)morpholine

To a solution of 4-fluoro-2-methoxy-1-nitrobenzene (750 mg, 4.38 mmol)in MeCN (10 mL) was added morpholine (3.83 mL, 43.8 mmol) and potassiumcarbonate (606 mg, 4.38 mmol). The reaction mixture was heated at 70° C.for 18 hours. The reaction mixture was concentrated in vacuo. Theresidue was dissolved in DCM (30 mL) and washed with water (2×30 mL),dried (MgSO₄) and concentrated in vacuo, to give the title compound (1.0g, 96%).

¹H NMR (500 MHz, CDCl₃): δ 8.03 (d, J=9.0 Hz, 1H), 6.48 (dd, J=9.0, 2.5Hz, 1H), 6.44 (d, J=2.5 Hz, 1H), 3.98 (s, 3H), 3.90 (app, t, J=5.0 Hz,4H), 3.38 (app t, J=5.0 Hz, 4H).

LCMS (ESI) Rt=1.95 minutes MS m/z 239.28 [M+H]⁺

Preparation 79 2-methoxy-4-morpholinoaniline

To a solution of 4-(3-methoxy-4-nitrophenyl)morpholine (Preparation 78,1.00 g, 4.20 mmol) in EtOH (42 mL) was added tin (II) chloride (2.79 g,14.69 mmol). The reaction mixture was heated to 70° C. for 18 hours. Thereaction mixture was diluted with ice-water (10 mL) and concentrated invacuo. Aqueous Na₂CO₃ (2M, 20 mL) was added and the reaction mixture wasextracted with EtOAc (3×20 mL). The combined organic layers were washedwith brine (30 mL), dried (MgSO₄) and concentrated in vacuo. The residuewas purified by passage through a SCX-2 cartridge eluting with 100%MeOH—1M NH₃ in MeOH to give the title compound (418 mg, 48%).

¹H NMR (500 MHz, CDCl₃): δ 6.71-6.64 (m, 2H), 6.49 (m, 1H), 3.93 (t,J=5.5 Hz, 4H), 3.87 (s, 3H), 3.14-3.08 (m, 4H).

LCMS (ESI) Rt=0.60 minutes MS m/z 209.34 [M+H]⁺

Preparation 80 N-(2-methoxy-4-morpholinophenyl)formamide

The title compound was prepared according to Method 13 (Preparation 55)using 2-methoxy-4-morpholinoaniline (Preparation 79). The crude residuewas used directly in the next reaction.

¹H NMR (500 MHz, MeOD): δ 8.24 (s, 1H), 7.98 (d, J=8.5 Hz, 1H), 6.65 (d,J=2.5 Hz, 1H), 6.52 (dd, J=8.5, 2.5 Hz, 1H), 3.89 (s, 3H), 3.85-3.83 (m,4H), 3.15-3.13 (m, 4H).

LCMS (ESI) Rt=1.49 minutes MS m/z 237.32 [M+H]⁺

Preparation 81 4-(6-methoxy-5-nitropyridin-2-yl)morpholine

To a solution of 6-chloro-2-methoxy-3-nitropyridine (283 mg, 1.5 mmol)in acetonitrile/DMF (2:1, 3 mL) was added morpholine (0.13 mL, 1.5 mmol)and triethylamine (0.21 mL, 1.5 mmol). The reaction mixture was stirredat room temperature for 18 hours. The reaction mixture was concentratedin vacuo and the residue was partitioned between water (30 mL) and EtOAc(30 mL). The organic layer was dried (MgSO₄) and concentrated in vacuo.The residue was purified by silica gel column chromatography elutingwith 20% cyclohexane in EtOAc to give the title compound (280 mg, 78%).¹H NMR (500 MHz, CDCl₃): δ 8.28 (d, J=9.0 Hz, 1H), 6.16 (d, J=9.0 Hz,1H), 4.04 (s, 3H), 3.82 (t, J=4.5 Hz, 4H), 3.71 (t, J=4.5 Hz, 4H).

LCMS (ESI) Rt=1.96 minutes MS m/z 240.11 [M+H]⁺

Preparation 82 2-methoxy-6-(methylthio)-3-nitropyridine

To a solution of 6-chloro-2-methoxy-3-nitropyridine (300 mg, 1.591 mmol)in acetonitrile/DMF (2:1, 3 mL) was added sodium thiomethoxide (133 mg,1.91 mmol). The reaction mixture was stirred at room temperature for 18hours and then concentrated in vacuo. The residue was partitionedbetween water (30 mL) and EtOAc (30 mL). The organic layer was dried(MgSO₄) and concentrated in vacuo to give the title compound (290 mg,91%).

¹H NMR (500 MHz, CDCl₃): δ 8.17 (d, J=8.5 Hz, 1H), 6.85 (d, J=8.5 Hz,1H), 4.12 (s, 3H), 2.62 (s, 3H).

LCMS (ESI) Rt=2.42 minutes MS m/z 201.07 [M+H]⁺

Preparation 83 2-methoxy-6-(methylsulfonyl)-3-nitropyridine

To a solution of 2-methoxy-6-(methylthio)-3-nitropyridine (Preparation82, 290 mg, 1.45 mmol) in DCM (10 mL) was added mCPBA (650 mg, 3.2mmol). The reaction mixture was stirred at room temperature for 3 hours.The reaction mixture was diluted with DCM (30 mL) and washed withaqueous saturated NaHCO₃ (30 mL), water (30 mL) and brine (30 mL), dried(MgSO₄) and concentrated in vacuo to give the title compound (290 mg,86%).

¹H NMR (500 MHz, CDCl₃): δ 8.44 (d, J=8.0 Hz), 7.8 (d, J=8.0 Hz, 1H),4.19 (s, 3H), 3.25 (s, 3H).

LCMS (ESI) Rt=1.48 minutes MS m/z 233.03 [M+H]⁺

Preparation 84 Methyl 2-(benzyloxy)-5-bromoisonicotinate

To a suspension of methyl5-bromo-2-oxo-1,2-dihydropyridine-4-carboxylate (2.5 g, 10.77 mmol) inMeCN (35 mL) was added silver carbonate (4.46 g, 16.16 mmol) and benzylbromide (1.54 mL, 12.93 mmol). The reaction mixture was heated to 65° C.and stirred for 18 hours. The reaction mixture was filtered through aplug of Celite® and concentrated in vacuo. The residue was purified bysilica gel column chromatography eluting with 50-100% DCM in cyclohexaneto give the title compound (3.31 g, 95%).

¹H NMR (500 MHz, CDCl₃): δ 8.38 (s, 1H), 7.45 (dd, J=8.0, 2.0 Hz, 2H),7.41-7.38 (m, 2H), 7.34 (m, 1H), 7.17 (m, 1H), 5.39 (s, 2H), 3.96 (s,3H).

LCMS (ESI) Rt=3.04 minutes MS m/z 321.97 [M+H]⁺

Preparation 85 (E)-methyl 2-(benzyloxy)-5-(2-ethoxyvinyl)isonicotinate

To a suspension of methyl 2-(benzyloxy)-5-bromoisonicotinate(Preparation 84, 1.5 g, 4.66 mmol),(E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Preparation 29, 1.844 g, 9.31 mmol) and Na₂CO₃ (0.99 g, 9.31 mmol) intoluene (5 mL), EtOH (5 mL) and water (5 mL) was added Pd(PPh₃)₄ (377mg, 0.326 mmol). The reaction mixture was heated to 70° C. for 18 hours,under nitrogen. The reaction mixture was diluted with EtOAc (75 mL) andwater (75 mL). The organic layer was dried (MgSO₄) and concentrated invacuo. The residue was purified by silica gel column chromatographyeluting with 0-10% EtOAc in cyclohexane to give the title compound (1.2g, 82%). 1H NMR (500 MHz, CDCl₃): δ 8.23 (s, 1H), 7.47 (d, J=7.5, 1.5Hz, 2H), 7.39 (td, J=8.5, 2.5 Hz, 2H), 7.33 (m, 1H), 7.24 (s, 1H), 6.80(d, J=13.0 Hz, 1H), 6.39 (d, J=13.0 Hz, 1H), 5.40 (s, 2H), 3.95 (q,J=7.5 Hz, 2H), 3.92 (s, 3H), 1.37 (t, J=7.5 Hz, 3H).

LCMS (ESI) Rt=3.09 minutes MS m/z 314.27 [M+H]⁺

Preparation 86 7-(benzyloxy)-2,6-naphthyridin-1-ol

(E)-methyl 2-(benzyloxy)-5-(2-ethoxyvinyl)isonicotinate (Preparation 85,1.2 g, 3.83 mmol) was dissolved in methanolic ammonia (7M, 28 mL) in 3microwave tubes. The reaction mixture was sealed and heated to 80° C.for 3 days. The reaction mixture was concentrated in vacuo. The residuewas dissolved in toluene (30 mL) and pTsOH.H₂O (150 mg, 0.789 mmol) wasadded. The reaction mixture was heated at 90° C. for 2 hours. Thereaction mixture was filtered and dried under vacuum, to give the titlecompound (937 mg, 97%).

¹H NMR (500 MHz, CDCl₃): δ 10.20 (br s, 1H), 8.68 (s, 1H), 7.70 (s, 1H),7.50 (d, J=7.5 Hz, 2H), 7.40 (t, J=7.5 Hz, 2H), 7.34 (m, 1H), 7.03 (m,1H), 6.61 (d, J=7.0 Hz, 1H), 5.50 (s, 2H).

LCMS (ESI) Rt=2.47 minutes MS m/z 253.33 [M+H]⁺

Preparation 87 7-(benzyloxy)-2,6-naphthyridin-1-yltrifluoromethanesulfonate

To a suspension of 7-(benzyloxy)-2,6-naphthyridin-1-ol (Preparation 86,450 mg, 1.784 mmol) in DCM (20 mL) was added Et₃N (0.50 mL, 3.57 mmol)and trifluoromethanesulfonic anhydride (0.36 mL, 2.141 mmol). Thereaction mixture was stirred at room temperature under for 2.5 hours.The reaction mixture was concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluting with 50-80% DCM to give thetitle compound (415 mg, 58%).

¹H NMR (500 MHz, CDCl₃): δ 9.13 (s, 1H), 8.14 (d, J=6.0 Hz, 1H), 7.76(dd, J=6.0, 1.0 Hz, 1H), 7.52 (d, J=7.5 Hz, 2H), 7.43-7.39 (m, 2H), 7.37(m, 1H), 7.31 (s, 1H), 5.56 (s, 2H).

LCMS (ESI) Rt=3.15 minutes MS m/z 385.28 [M+H]⁺

Preparation 887-(benzyloxy)-1-(1-methyl-1H-pyrazol-4-yl)-2,6-naphthyridine

To a suspension of 7-(benzyloxy)-2,6-naphthyridin-1-yltrifluoromethanesulfonate (Preparation 87, 350 mg, 0.911 mmol) in1,4-dioxane (6 mL) and water (3 mL) was added 1-Methylpyrazole-4-boronicacid pinacol ester (379 mg, 1.821 mmol), cesium carbonate (460 mg, 1.412mmol) and Pd(PPh₃)₄ (220 mg, 0.190 mmol). The reaction mixture washeated to 100° C. for 30 minutes under microwave conditions. Thereaction mixture was diluted with EtOAc (25 mL) and water (25 mL). Theorganic layer was dried (MgSO₄) and concentrated in vacuo. The residuewas purified by silica gel column chromatography eluting with 0-15% MeOHin DCM followed by a second chromatography eluting with 0-10% MeOH inDCM to give the title compound (249 mg, 86%).

¹H NMR (500 MHz, CDCl₃): δ 9.04 (d, J=1.0 Hz, 1H), 8.47 (d, J=6.0 Hz,1H), 8.02 (s, 1H), 7.93 (s, 1H), 7.58-7.54 (m, 2H), 7.53-7.51 (m, 2H),7.44-7.40 (m, 2H), 7.36 (m, 1H), 5.53 (s, 2H), 4.04 (s, 3H).

LCMS (ESI) Rt=2.60 minutes MS m/z 317.28 [M+H]⁺

Preparation 89 5-(1-methyl-1H-pyrazol-4-yl)-2,6-naphthyridin-3-ol

A solution of Pd(OAc)₂ (4 mg, 0.019 mmol), Et₃N (7.5 uL, 0.053 mmol),triethylsilane (0.085 mL, 0.531 mmol) in DCM (8 mL) was stirred at roomtemperature for 10 minutes. A solution of7-(benzyloxy)-1-(1-methyl-1H-pyrazol-4-yl)-2,6-naphthyridine(Preparation 88, 120 mg, 0.379 mmol) in DCM (1 mL) was added. Thereaction mixture was stirred at room temperature for 18 hours. Thereaction mixture was quenched with aqueous saturated ammonium chloride(20 mL) and extracted with ether (2×30 mL). The combined organic layerswere dried (MgSO₄) and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluting with 0-10% MeOH in DCM togive the title compound (13 mg, 15%).

¹H NMR (500 MHz, CDCl₃): δ 8.91 (s, 1H), 8.46 (d, J=5.5 Hz, 1H), 8.09(s, 1H), 8.00 (s, 1H), 7.57-7.55 (m, 2H), 4.06 (s, 3H).

LCMS (ESI) Rt=1.10 minutes MS m/z 227.12 [M+H]⁺

Preparation 90 5-(1-methyl-1H-pyrazol-4-yl)-2,6-naphthyridin-3-yltrifluoromethanesulfonate

To a solution of 5-(1-methyl-1H-pyrazol-4-yl)-2,6-naphthyridin-3-ol(Preparation 89, 15 mg, 0.066 mmol) in DCM (0.5 mL) was added Tf₂O(0.013 mL, 0.080 mmol) and triethylamine (9.3 uL, 0.066 mmol). Thereaction mixture was stirred at room temperature under 1 hour. Thereaction mixture was concentrated in vacuo. The residue was passedthrough a SCX-2 cartridge eluting with 100% MeOH—1M NH₃ in MeOH to givethe title compound (14 mg, 59%).

1H NMR (500 MHz, CDCl₃): δ 9.18 (s, 1H), 8.78 (d, J=5.5 Hz, 1H), 8.06(s, 1H), 7.75 (dd, J=5.5, 1.0 Hz, 1H), 7.48 (s, 1H), 7.07 (s, 1H), 4.09(s, 3H).

LCMS (ESI) Rt=2.52 minutes MS m/z 358.96 [M+H]⁺

Preparation 91 7-(benzyloxy)-N-cyclohexyl-2,6-naphthyridin-1-amine

To a solution of 7-(benzyloxy)-2,6-naphthyridin-1-yltrifluoromethanesulfonate (Preparation 87, 130 mg, 0.338 mmol) in NMP (6mL) was added cyclohexylamine (0.39 mL, 3.38 mmol). The reaction mixturewas heated to 120° C. for 30 minutes. The reaction was quenched with aq.sat. NaHCO₃ (30 mL) and extracted with EtOAc (2×30 mL). The combinedorganic layers were washed with water (40 mL) and brine (30 mL), dried(MgSO₄) and concentrated in vacuo. The residue was purified by silicagel column chromatography eluting with 0-10% MeOH in DCM to give thetitle compound (70 mg, 62%).

¹H NMR (500 MHz, CDCl₃): δ 8.78 (s, 1H), 7.90 (d, J=6.0 Hz, 1H),7.51-7.48 (m, 2H), 7.41-7.38 (m, 2H), 7.34 (m, 1H), 6.97 (s, 1H), 6.91(d, J=6.0 Hz, 1H), 5.51 (s, 2H), 4.99 (br d, J=7.0 Hz, 1H), 4.16 (m,1H), 2.16-2.14 (m, 2H), 1.81-1.76 (m, 2H), 1.54-1.47 (m, 2H), 1.32-1.25(m, 4H).

LCMS (ESI) Rt=2.11 minutes MS m/z 334.11 [M+H]⁺

Preparation 92 5-(cyclohexylamino)-2,6-naphthyridin-3-ol

The title compound was prepared according to the method described forPreparation 89 using 7-(benzyloxy)-N-cyclohexyl-2,6-naphthyridin-1-amine(Preparation 91).

¹H NMR (500 MHz, CDCl₃): δ 8.46 (s, 1H), 7.79 (d, J=6.0 Hz, 1H), 6.87(s, 1H), 6.79 (d, J=6.0 Hz, 1H), 5.03 (d, J=7.5 Hz, 1H), 4.16 (m, 1H),2.18-2.14 (m, 2H), 1.83-1.78 (m, 2H), 1.70 (m, 2H), 1.64-1.48 (m, 2H),1.35-1.28 (m, 2H).

LCMS (ESI) Rt=1.18 minutes MS m/z 244.14 [M+H]⁺

Preparation 93 5-(cyclohexylamino)-2,6-naphthyridin-3-yltrifluoromethanesulfonate

The title compound was prepared according to the method described forPreparation 90 using 5-(cyclohexylamino)-2,6-naphthyridin-3-ol(Preparation 92).

¹H NMR (500 MHz, CDCl₃): δ 8.88 (d, J=0.5 Hz, 1H), 8.18 (d, J=5.5 Hz,1H), 7.40 (s, 1H), 7.03 (dd, J=5.5, 1.0 Hz, 1H), 5.11 (br d, J=7.5 Hz,1H), 4.19 (m, 1H), 2.20-2.16 (m, 2H), 1.84 (dt, J=13.0, 3.5 Hz, 2H),1.73 (dt, J=13.0, 3.5 Hz, 2H), 1.51 (m, 2H), 1.37-1.30 (m, 2H).

LCMS (ESI) Rt=2.50 minutes MS m/z 375.99 [M+H]⁺

Preparation 947-(benzyloxy)-N-(cyclopropylmethyl)-2,6-naphthyridin-1-amine

The title compound was prepared according to the method described forPreparation 91 using cyclopropanemethylamine.

¹H NMR (500 MHz, CDCl₃): δ 8.80 (d, J=0.5 Hz, 1H), 7.90 (d, J=6.0 Hz,1H), 7.52-7.50 (m, 2H), 7.42-7.39 (m, 2H), 7.35 (m, 1H), 7.05 (s, 1H),6.94 (dd, J=6.0, 0.5 Hz, 1H), 5.52 (s, 2H), 5.23 (br s, 1H), 3.43 (dd,J=7.0, 5.0 Hz, 2H), 1.19 (m, 1H), 0.63-0.59 (m, 2H), 0.35-0.31 (m, 2H).

LCMS (ESI) Rt=1.96 minutes MS m/z 306.11 [M+H]⁺

Preparation 95 5-((cyclopropylmethyl)amino)-2,6-naphthyridin-3-ol

The title compound was prepared according to the method described forPreparation 89 using7-(benzyloxy)-N-(cyclopropylmethyl)-2,6-naphthyridin-1-amine(Preparation 94).

¹H NMR (500 MHz, CDCl₃): δ 8.46 (s, 1H), 7.81 (d, J=7.5 Hz, 1H), 6.96(s, 1H), 6.83 (d, J=6.5 Hz, 1H), 5.29 (br s, 1H), 3.44 (dd, J=7.0, 5.0Hz, 2H), 1.22 (m, 1H), 0.63 (q, J=5.5 Hz, 2H), 0.35 (q, J=5.5 Hz, 2H).

LCMS (ESI) Rt=0.84 minutes MS m/z 216.14 [M+H]⁺

Preparation 96 5-((cyclopropylmethyl)amino)-2,6-naphthyridin-3-yltrifluoromethanesulfonate

The title compound was prepared according to the method described forPreparation 90 using 5-((cyclopropylmethyl)amino)-2,6-naphthyridin-3-ol(Preparation 95).

¹H NMR (500 MHz, CDCl₃): δ 8.91 (d, J=0.5 Hz, 1H), 8.18 (d, J=6.0 Hz,1H), 7.51 (s, 1H), 7.06 (dd, J=6.0, 0.5 Hz, 1H), 5.46 (br t, J=5.0 Hz,1H), 3.47 (dd, J=7.0, 5.0 Hz, 2H), 1.22 (m, 1H), 0.67-0.63 (m, 2H),0.38-0.34 (m, 2H).

LCMS (ESI) Rt=2.22 minutes MS m/z 347.99 [M+H]⁺

Preparation 97 8-chloro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine

A suspension of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine(Preparation 33, 71 mg, 0.335 mmol) in DCM (3 mL) was treated with mCPBA(77% w/w, 180 mg, 0.801 mmol) at 0° C. and then allowed to reach roomtemperature for 18 hours. The mixture was quenched with water andextracted with DCM. The combined organic layers were washed with water,dried and concentrated. The residue was purified by silica gel columnchromatography eluting with 0 to 80% EtOAc in cyclohexane to give thetitle compound (55 mg, 67%).

¹H NMR (500 MHz, CDCl₃) δ 9.76 (s, 1H), 8.77 (d, J=5.5 Hz, 1H), 7.89 (d,J=5.5 Hz, 1H), 3.59 (s, 3H).

LCMS (ESI) Rt=1.31 minutes MS m/z 266 [M+Na]⁺

Preparation 98 2-methyl-4-(1-methyl-1H-pyrazol-4-yl)aniline

To a solution of 4-bromo-2-methylaniline (500 mg, 2.69 mmol) in EtOH (10mL), toluene (10 mL) and water (10 mL) was added1-methylpyrazole-4-boronic acid pinacol ester (671 mg, 3.22 mmol),sodium carbonate (570 mg, 5.37 mmol) and Pd(PPh₃)₄ (373 mg, 0.322 mmol).The reaction mixture was heated to 80° C. for 2.5 hours. The reactionmixture was cooled to room temperature and diluted with EtOAc (30 mL),washed with water (30 mL) and brine (30 mL), dried (MgSO₄) andconcentrated in vacuo. The residue was purified by passage through aSCX-2 cartridge eluting with 100% MeOH—1M NH₃ in MeOH. The residue waspurified by silica gel column chromatography eluting with 0-10% MeOH inDCM to give the title compound (106 mg, 21%).

¹H NMR (500 MHz, CDCl₃) 7.68 (s, 1H), 7.51 (s, 1H), 7.19 (m, 1H), 7.16(dd, J=8.0, 2.0 Hz, 1H), 6.69 (d, J=8.0 Hz, 1H), 3.93 (s, 3H), 3.62 (brs, 2H), 2.22 (s, 3H).

LCMS (ESI) Rt=0.98 minutes MS m/z 188.17 [M+H]⁺

Preparation 99 N-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide

A solution of 2-methyl-4-(1-methyl-1H-pyrazol-4-yl)aniline (Preparation98, 100 mg, 0.534 mmol) in formic acid (3 mL) was heated to reflux for 3hours. The reaction mixture was concentrated in vacuo. The residue waspartitioned between aqueous saturated NaHCO₃ solution (30 mL) and EtOAc(30 mL). The aqueous layer was re-extracted with EtOAc (30 mL). Thecombined organic layers were washed with water (30 mL) and brine (30mL)), dried (MgSO₄) and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluting with 0-10% MeOH in EtOAc togive the title compound (160 mg, 34%).

¹H NMR (500 MHz, MeOD): δ 8.31 (s, 1H), 7.93 (s, 1H), 7.80 (s, 1H), 7.67(d, J=8.0 Hz, 1H), 7.44 (d, J=2.0 Hz, 1H), 7.38 (dd, J=8.0, 2.0, Hz,1H), 3.92 (s, 3H), 2.31 (s, 3H).

LCMS (ESI) Rt=1.72 minutes MS m/z 216.13 [M+H]⁺

Preparation 100 4-bromo-2-ethoxy-1-nitrobenzene

To a cooled (0° C.) solution of EtOH (0.07 mL, 1.193 mmol) in THF (5 mL)was added NaH (60% suspension in mineral oil, 68 mg, 1.705 mmol). Thereaction mixture was stirred under nitrogen at 0° C. for 15 minutes.2-fluoro-4-bromo-nitrobenzene (250 mg, 1.136 mmol) was added and thereaction mixture stirred for a further 18 hours, whilst warming slowlyto room temperature. The reaction mixture was concentrated in vacuo.Ether (20 mL) and HCl (0.5 M, 20 mL) were added. The aqueous layer wasbasified with aqueous saturated NaHCO₃ solution and extracted with EtOAc(3×20 mL). The combined organic layers were washed with brine (20 mL),dried (MgSO₄) and concentrated in vacuo, to give the title compound (270mg, 97%).

¹H NMR (500 MHz, CDCl₃): δ 7.74 (d, J=8.5 Hz, 1H), 7.24 (d, J=2.0 Hz,1H), 7.17 (dd, J=8.5, 2.0 Hz, 1H), 4.19 (q, J=7.0 Hz, 2H), 1.50 (t,J=7.0 Hz, 3H).

Preparation 101 1 4-bromo-2-ethoxyaniline

To a solution of 4-bromo-2-ethoxy-1-nitrobenzene (Preparation 100, 250mg, 1.016 mmol) in EtOH (15 mL) was added tin (II) chloride (963 mg,5.08 mmol). The reaction mixture was heated to 70° C. for 2 hours. Thereaction mixture was diluted with ice-water (10 mL) and concentrated invacuo. Aqueous Na₂CO₃ (2M, 20 mL) was added and the reaction mixture wasextracted with EtOAc (3×20 mL). The combined organic layers were washedwith brine (30 mL), dried (MgSO₄) and concentrated in vacuo. The residuewas purified by passage through a SCX-2 cartridge eluting with 100%MeOH—1M NH₃ in MeOH to give the title compound (179 mg, 82%).

1H NMR (500 MHz, CDCl₃): δ 6.91-6.88 (m, 2H), 6.60 (dd, J=8.0, 0.5 Hz,1H), 4.05 (q, J=7.0 Hz, 2H), 1.45 (t, J=7.0 Hz, 3H).

LCMS (ESI) Rt=1.96 minutes MS m/z 216.01 [M+H]⁺

Preparation 102 2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline

The title compound was prepared according to Preparation 98 using4-bromo-2-ethoxyaniline (Preparation 101).

¹H NMR (500 MHz, CDCl₃): δ 7.67 (d, J=0.5 Hz, 1H), 7.51 (s, 1H), 6.92(d, J=2.0 Hz, 1H), 6.90 (dd, J=7.5, 2.0 Hz, 1H), 6.73 (d, J=7.5 Hz, 1H),4.12 (q, J=7.0 Hz, 2H), 3.94 (s, 3H), 3.81 (br s, 2H), 1.47 (t, J=7.0Hz, 3H).

LCMS (ESI) Rt=1.18 minutes MS m/z 218.16 [M+H]⁺

Preparation 103 N-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide

The title compound was prepared according to Preparation 99 using2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline (Preparation 102).

¹H NMR (500 MHz, CDCl₃): δ 8.49 (d, J=2.0 Hz, 1H), 8.37 (d, J=8.5 Hz,1H), 7.81 (br s, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 7.07 (dd, J=8.5, 2.0Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.96 (s, 3H),1.51 (t, J=7.0 Hz, 3H).

LCMS (ESI) Rt=1.96 minutes MS m/z 246.12 [M+H]⁺

Preparation 104 4-bromo-2-isopropoxy-1-nitrobenzene

The title compound was prepared according to Preparation 100 using2-propanol.

¹H NMR (500 MHz, CDCl₃): δ 7.69 (d, J=8.5 Hz, 1H), 7.23 (d, J=2.0 Hz,1H), 7.14 (dd, J=8.5, 2.0 Hz, 1H), 4.67 (quin, J=6 Hz, 1H), 1.43 (s,3H), 1.42 (s, 3H).

Preparation 105 4-bromo-2-isopropoxyaniline

The title compound was prepared according to Preparation 101 using4-bromo-2-isopropoxy-1-nitrobenzene (Preparation 104).

¹H NMR (500 MHz, MeOD): δ 7.03 (d, J=2.0 Hz, 1H), 6.91 (dd, J=8.5, 2.0Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 4.60 (quin, J=6.0 Hz, 1H), 1.36 (s,3H), 1.35 (s, 3H).

LCMS (ESI) Rt=2.22 minutes MS m/z 230.03 [M+H]⁺

Preparation 106 2-isopropoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline

The title compound was prepared according to Preparation 98 using4-bromo-2-isopropoxyaniline (Preparation 105).

¹H NMR (500 MHz, CDCl₃): δ 7.66 (d, J=0.5 Hz, 1H), 7.50 (s, 1H), 6.92(s, 1H), 6.91 (dd, J=7.5, 2.0 Hz, 1H), 6.73 (d, J=7.5 Hz, 1H), 4.59(quin, J=6.0 Hz, 1H), 3.94 (s, 3H), 3.80 (br s, 2H), 1.40 (s, 3H), 1.39(s, 3H).

LCMS (ESI) Rt=1.36 minutes MS m/z 232.18 [M+H]⁺

Preparation 107N-(2-isopropoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide

The title compound was prepared according to Preparation 99 using2-isopropoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline (Preparation 106).

¹H NMR (500 MHz, CDCl₃): δ 8.48 (d, J=2.0 Hz, 1H), 8.38 (d, J=8.5 Hz,1H), 7.81 (br s, 1H), 7.71 (s, 1H), 7.59 (s, 1H), 7.05 (dd, J=8.5, 2.0Hz, 1H), 4.69 (quin, J=6.0 Hz, 1H), 3.96 (s, 3H), 1.42 (d, J=6.0 Hz,3H), 1.40 (d, J=6.0 Hz, 3H).

LCMS (ESI) Rt=2.03 minutes MS m/z 260.14 [M+H]⁺

Preparation 108 4-bromo-2-(2-methoxyethoxy)-1-nitrobenzene

The title compound was prepared according to Preparation 100 using2-methoxyethanol.

¹H NMR (500 MHz, CDCl₃): δ 7.76 (d, J=8.5 Hz, 1H), 7.30 (d, J=2.0 Hz,1H), 7.20 (dd, J=8.5, 2.0 Hz, 1H), 4.26 (dd, J=5.0, 4.0 Hz, 2H), 3.82(dd, J=5.0, 4.0 Hz, 2H), 3.47 (s, 3H).

Preparation 109 4-bromo-2-(2-methoxyethoxy)aniline

The title compound was prepared according to Preparation 101 using4-bromo-2-(2-methoxyethoxy)-1-nitrobenzene (Preparation 108).

¹H NMR (500 MHz, MeOD): δ 6.99 (d, J=2.0 Hz, 1H), 6.89 (dd, J=8.5, 2.0Hz, 1H), 6.68 (d, J=8.5 Hz, 1H), 4.14-4.12 (m, 2H), 3.78-3.76 (m, 2H),3.45 (s, 3H).

LCMS (ESI) Rt=1.73 minutes MS m/z 246.02 [M+H]⁺

Preparation 110 2-(2-methoxyethoxy)-4-(1-methyl-1H-pyrazol-4-yl)aniline

The title compound was prepared according to Preparation 98 using4-bromo-2-(2-methoxyethoxy)aniline (Preparation 109).

¹H NMR (500 MHz, CDCl₃): δ 7.67 (d, J=0.5 Hz, 1H), 7.50 (s, 1H), 6.95(dd, J=7.5, 2.0 Hz, 1H), 6.94 (s, 1H), 6.73 (dd, J=7.5, 1.5 Hz, 1H),4.21-4.19 (m, 2H), 3.94 (s, 3H), 3.87 (br s, 2H), 3.80-3.78 (m, 2H),3.47 (s, 3H).

LCMS (ESI) Rt=1.15 minutes MS m/z 248.16 [M+H]⁺

Preparation 111N-(2-(2-methoxyethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide

The title compound was prepared according to Preparation 99 using2-(2-methoxyethoxy)-4-(1-methyl-1H-pyrazol-4-yl)aniline (Preparation110).

¹H NMR (500 MHz, CDCl₃): δ 8.47 (d, J=2.0 Hz, 1H), 8.38 (d, J=8.5 Hz,1H), 8.08 (br s, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 7.12 (dd, J=8.5, 2.0Hz, 1H), 7.05 (m, 1H), 4.26-4.23 (m, 2H), 3.96 (s, 3H), 3.79-3.77 (m,2H), 3.48 (s, 3H).

Preparation 1121-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

NaH (60%, 128 mg) was added to a solution of4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (313 mg,1.61 mmol) in DMF (4 mL). After stirring for 15 minutes,1,1-difluoro-2-iodoethane (372 mg, 1.94 mmol) in DMF (1 mL) was added.The resulting solution was stirred at 80° C. under microwave irradiationfor 60 minutes. The reaction mixture was diluted with brine andextracted with EtOAc. The combined organic layers were washed withwater, dried with Na₂SO₄, and concentrated in vacuo to afford the titlecompound as a yellow oil that was used directly in the next step (210mg, 50%).

¹H NMR (500 MHz, CDCl₃): δ 7.84 (d, J=0.7 Hz, 1H), 7.77 (d, J=0.7 Hz,1H), 6.25-5.93 (m, 1H), 4.57-4.39 (m, 2H), 1.33 (s, 12H).

LCMS (ESI) Rt=2.64 minutes MS m/z 259 [M+H]⁺

Preparation 1138-chloro-N-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine

To a cooled (0° C.) suspension ofN-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide (Preparation99, 40 mg, 0.186 mmol) in THF (4 mL) was added NaH (60% dispersion inoil, 12 mg, 0.297 mmol). The reaction mixture was stirred at roomtemperature for 10 minutes. The reaction mixture was cooled to 0° C. and8-chloro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 97, 59mg, 0.242 mmol) was added. The reaction mixture was stirred for 18hours, whilst slowly warming to room temperature. The reaction mixturewas concentrated in vacuo. The residue was partitioned between EtOAc (30mL) and water (30 mL). The aqueous layer was extracted with EtOAc (30mL) and DCM (30 mL). The combined organic layers were washed with water(30 mL) and brine (30 mL), dried (MgSO₄) and concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluting with0-5% MeOH in EtOAc to give the title compound (79 mg, 97%).

¹H NMR (500 MHz, CDCl₃):δ 9.17 (s, 1H), 8.26 (d, J=5.0 Hz, 1H), 7.79 (s,1H), 7.63 (s, 1H), 7.52 (d, J=5.0 Hz, 1H), 7.47 (dd, J=8.0, 2.0 Hz, 1H),7.42 (m, 1H), 7.39 (d, J=2.0 Hz, 1H), 3.98 (s, 3H), 2.44 (s, 3H).

LCMS (ESI) Rt=2.56 minutes MS m/z 351.02 [M+H]⁺

Preparation 1148-chloro-N-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine

The title compound was prepared according to the method described forPreparation 113 usingN-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide (Preparation103). The residue was purified by silica gel column chromatographyeluting with 50-100% EtOAc in cyclohexane to give the title compound (27mg, 44%).

¹H NMR (500 MHz, CDCl₃): δ 9.17 (s, 1H), 9.07 (br s, 1H), 8.33 (br s,1H), 8.26 (d, J=5.0 Hz, 1H), 7.78 (d, J=0.5 Hz, 1H), 7.63 (s, 1H), 7.52(d, J=5.0 Hz, 1H), 7.25 (dd, J=8.5, 2.0 Hz, 1H), 7.05 (d, J=2.0 Hz, 1H),4.25 (q, J=7.0 Hz, 2H), 3.98 (s, 3H), 1.56 (t, J=7.0 Hz, 3H).

LCMS (ESI) Rt=2.88 minutes MS m/z 381.01 [M+H]⁺

Preparation 1158-chloro-N-(2-isopropoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine

The title compound was prepared according to the method described forPreparation 113 usingN-(2-isopropoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide(Preparation 107). The residue was purified by silica gel columnchromatography eluting with 50-80% EtOAc in cyclohexane to give thetitle compound (37.7 mg, 62%).

¹H NMR (500 MHz, CDCl₃):δ 9.16 (s, 1H), 9.07 (br s, 1H), 8.34 (br s,1H), 8.26 (d, J=5.5 Hz, 1H), 7.77 (s, 1H), 7.62 (s, 1H), 7.52 (d, J=5.5Hz, 1H), 7.52 (m, 1H), 7.24 (dd, J=8.0, 2.0 Hz, 1H), 7.07 (d, J=2.0 Hz,1H), 4.76 (quin, J=6.0 Hz, 1H), 3.98 (s, 3H), 1.48 (s, 3H), 1.47 (s,3H).

LCMS (ESI) Rt=2.93 minutes MS m/z 395.02 [M+H]⁺

Preparation 1168-chloro-N-(2-(2-methoxyethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine

The title compound was prepared according to the method described forPreparation 113 usingN-(2-(2-methoxyethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide(Preparation 111). The residue was purified by silica gel columnchromatography eluting with 50-100% EtOAc in cyclohexane—5% MeOH inEtOAc to give the title compound (18 mg, 30%).

¹H NMR (500 MHz, CDCl₃): δ 9.17 (s, 1H), 9.08 (br s, 1H), 8.56 (s, 1H),8.26 (d, 1H), 7.78 (s, 1H), 7.63 (s, 1H), 7.52 (d, J=5.5 Hz, 1H), 7.29(dd, J=8.5, 2.0 Hz, 1H), 7.12 (d, J=2.0 Hz, 1H), 4.33-4.31 (m, 2H), 3.98(s, 3H), 3.86-3.84 (m, 2H), 3.53 (s, 3H).

LCMS (ESI) Rt=2.68 minutes MS m/z 410.97 [M+H]⁺

MPS1 IC50 (uM):

Preparation 1178-chloro-N-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)pyrido[3,4-d]pyrimidin-2-amine

Method 14

A solution ofN-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide(Preparation 77, 240 mg, 0.978 mmol) in THF (8 mL) was treated withsodium hydride (60% w/w, 65 mg, 1.625 mmol) at 0° C. After stirring for20 minutes at room temperature the mixture was cooled to 0° C. and8-chloro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 97, 325mg, 1.334 mmol) was added. The reaction was allowed to reach roomtemperature and stirred for 18 hours. A solution of aqueous 2M NaOH (4mL) and MeOH (4 mL) were added and the resulting mixture stirred at roomtemperature for 1 hour before concentrating in vacuo. The residue waspartitioned between DCM and water. The aqueous layer was extracted withDCM and the combined organic layers were dried and concentrated invacuo. The residue was purified by silica gel column chromatographyeluting with 0-100% EtOAc in cyclohexanes to give the title compound(362 mg, 97%).

¹H NMR (500 MHz, DMSO-d₆): δ 9.47 (s, 1H), 8.85 (br. s, 1H), 8.54 (br.s, 1H), 8.25 (d, J=5.2 Hz, 1H), 7.86 (d, J=5.2 Hz, 1H), 7.63 (s, 1H),7.09 (d, J=1.8 Hz, 1H), 7.06 (dd, J=8.2, 1.9 Hz, 1H), 3.93 (s, 3H), 3.79(s, 3H), 2.42 (s, 3H).

LCMS (ESI) Rt=3.10 minutes MS m/z 381 [M+H]⁺

The following Preparations were prepared according to Method 14 usingthe appropriate formamide and pyrido[3,4-d]pyrimidine as describedbelow. The crude reaction residues were purified as described oraccording to one of the following methods:

-   Method A: Silica gel column chromatography eluting with 0-10% MeOH    in DCM or EtOAc.-   Method B: Silica gel column chromatography eluting with 0 to 40%    EtOAc in cyclohexanes followed by preparative HPLC eluting with 40%    to 100% MeOH in H₂O (0.1% formic acid).

Preparation No Name/Structure Data 118

¹H NMR (500 MHz, DMSO-d₆): δ 9.63 (s, 1H), 8.96 (s, 1H), 8.83 (br. d, J= 8.2 Hz, 1H), 8.57 (s, 1H), 8.12 (d, J = 1.2 Hz, 1H), 7.46 (d, J = 1.9Hz, 1H), 7.43 (dd, J = 8.3, 1.9 Hz, 1H), 3.99 (s, 3H), 3.81 (s, 3H),2.64 (d, J = 1.0 Hz, 3H). LCMS (ESI) Rt = 2.57 minutes MS m/z 382 [M +H]⁺ Using N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide (Preparation 221) and 8-chloro-5-methyl-2-(methylsulfonyl)pyrido[3,4- d]pyrimidine (Preparation 184) andpurification method A. 119

¹H NMR (500 MHz, DMSO-d₆): δ 9.47 (s, 1H), 8.83 (s, 1H), 8.53 (s, 1H),8.31- 8.20 (m, 2H), 7.93 (d, J = 0.8 Hz, 1H), 7.87 (d, J = 5.2 Hz, 1H),7.31 (d, J = 1.8 Hz, 1H), 7.28 (dd, J = 8.4, 1.8 Hz, 1H), 4.16 (q, J =7.3 Hz, 2H), 3.96 (s, 3H), 1.43 (t, J = 7.3 Hz, 3H). LCMS (ESI) Rt =3.07 minutes MS m/z 381 [M + H]⁺ Using N-(4-(1-ethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide (Preparation 128) and 8-chloro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 97). 120

¹H NMR (500 MHz, DMSO-d₆): δ 9.55 (s, 1H), 8.94 (s, 1H), 8.74 (br. d, J= 8.4 Hz, 1H), 8.31 (d, J = 5.2 Hz, 1H), 7.92 (d, J = 5.2 Hz, 1H), 7.36(dd, J = 8.3, 1.8 Hz, 1H), 7.33 (d, J = 1.7 Hz, 1H), 4.54 (br. s, 1H),4.26 (br. s, 3H), 3.96 (s, 3H), 3.87 (br. s, 1H), 3.25 (s, 3H). LCMS(ESI) Rt = 2.71 minutes MS m/z 400 [M + H]⁺ Using N-(2-methoxy-4-(3-methoxyazetidine-1- carbonyl)phenyl)formamide (Preparation 129) and8-chloro-2- (methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 97).121

¹H NMR (500 MHz, CDCl₃): 6 8.38 (s, 1H), 7.41 (s, 1H), 7.48 (s, 1H),7.12 (dd, J = 8.0, 2.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 6.88 (d, J =2.0 Hz, 1H), 4.03 (s, 3H), 3.71 (s, 3H), 2.90 (s, 3H), 2.70 (s, 3H).LCMS (ESI) Rt = 2.20 minutes MS m/z 395 [M + H]⁺ UsingN-(4-(1,2-dimethyl-1H-imidazol-5- yl)-2-methoxyphenyl)formamide(Preparation 55) and 8-chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 178) andpurification method A. 122

¹H NMR (500 MHz, CDCl₃): δ 9.36 (s, 1H), 8.40 (d, J = 5.5 Hz, 1H), 7.78(s, 1H), 7.64 (s, 1H), 7.51 (d, J = 5.5 Hz, 1H), 7.46 (m, 1H), 7.25 (dd,J = 8.5, 1.5 Hz, 1H), 7.04 (d, J = 1.5 Hz, 1H), 3.97 (s, 3H), 4.25 (q, J= 6.5 Hz, 2H), 1.56 (t, J = 6.5 Hz, 3H). LCMS (ESI) Rt = 2.93 minutes MSm/z 381[M + H]⁺ Using N-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide (Preparation 103) and 8-chloro-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 97) andpurification method A. 123

¹H NMR (500 MHz, DMSO): δ 9.46 (s, 1H), 8.81 (br. s, 1H), 8.40 (br. s,1H), 8.24 (d, J = 5.2 Hz, 1H), 7.86 (d, J = 5.3 Hz, 1H), 7.01 (d, J =1.8 Hz, 1H), 6.92 (dd, J = 8.2, 1.8 Hz, 1H), 4.02-3.92 (m, 2H), 3.90 (s,3H), 3.53-3.39 (m, 2H), 2.85-2.73 (m, 1H), 1.89-1.63 (m, 4H). LCMS (ESI)Rt = 3.17 minutes MS m/z 371 [M + H]⁺ UsingN-(2-methoxy-4-(tetrahydro-2H- pyran-4-yl)phenyl)formamide (Preparation154) and 8-chloro-2- (methylsulfonyl)pyrido[3,4-d]pyrimidine(Preparation 97) and purification method A.

Preparation 1248-chloro-N-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidin-2-amine

To a solution of8-chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation178, 31 mg, 0.120 mmol) in DMSO (5 mL) was addedN-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide(Preparation 150, 35.5 mg, 0.144 mmol) and Cs₂CO₃ (78 mg, 0.241 mmol).The reaction mixture was heated to 120° C. for 18 hours. The reactionmixture was cooled to room temperature and diluted with EtOAc (30 mL)and water (30 mL). The organic layer was washed with brine (30 mL),dried (MgSO₄) and concentrated in vacuo. The residue was purified bysilica gel column chromatography eluting with 50-100% EtOAc incyclohexanes followed by elution through an SCX-2 column using MeOH—1MNH₃ in MeOH to afford the title compound (12.9 mg, 27%).

¹H NMR (500 MHz, acetone-d6): δ 9.41 (s, 1H), 9.25 (d, J=8.0 Hz, 1H),8.50 (br s, 1H), 8.38 (s, 1H), 7.71 (d, J=1.0 Hz, 1H), 7.50 (s, 1H),7.49 (dd, J=8.0, 2.0 Hz, 1H), 4.38 (q, J=7.0 HZ, 2H), 3.93 (s, 3H), 2.62(d, J=1.0 Hz, 3H), 1.57 (t, J=7.0 Hz, 3H).

LCMS (ESI) Rt=2.91 minutes MS m/z 396 [M+H]⁺

Preparation 1258-Chloro-6-cyclopropyl-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine

N-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)formamide (Preparation56, 50 mg 0.21 mmole) was stirred in THF (1 mL). Sodiumhexamethyldisilazide (0.25 mL of 1M solution in THF) was added and thereaction stirred at room temperature for 20 minutes.8-Chloro-6-cyclopropyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine(Preparation 179, 80 mg, 0.28 mmole) was added as a suspension in THF(1.5 mL) and the reaction was stirred at room temperature for 80minutes. Methanol (1 mL) and 1M sodium hydroxide solution (1 mL) wereadded to the reaction and stirred for 55 minutes. The solvents were thenconcentrated in vacuo. The residue was partitioned between chloroform(10 mL) and water (10 mL). The layers were separated and the aqueous wasagain extracted with chloroform. The combined organic layers were driedand concentrated in vacuo. The residue was purified using preparativeTLC eluting with 1:1 acetone:cyclohexane to afford the title compound(41 mg 44%).

¹H NMR (500 MHz, CDCl₃): δ 9.08 (s, 1H), 9.03 (br d, J=8.20 Hz, 1H),8.24 (br s, 1H), 7.79 (s, 1H), 7.65 (s, 1H), 7.32 (s, 1H), 7.24 (dd,J=1.89, 8.51 Hz, 1H), 7.03 (d, J=1.58 Hz, 1H), 4.01 (s, 3H), 3.99 (s,3H), 2.14 (m, 1H), 1.04-1.13 (m, 4H).

Preparation 126N-(2-methoxy-6-(1-methyl-1H-tetrazol-5-yl)pyridin-3-yl)formamide

Method 15

Formic acid (59.3 μL, 1.571 mmol) was added to acetic anhydride (99 μL,1.048 mmol) while stirring and cooling at 0° C. Stirring was continuedfor 1 hour at room temperature. The reaction was cooled to 0° C. andadded to a solution of2-methoxy-6-(1-methyl-1H-tetrazol-5-yl)pyridin-3-amine (Preparation 158,18 mg, 0.087 mmol) in THF (100 μL) at 0° C. The reaction mixture wasstirred at room temperature for 30 hours. The residue was dissolved inDCM and the solution was washed with saturated aqueous NaHCO₃ solution.The organic layer was dried (Na₂SO₄), filtered and concentrated in vacuoto afford the title compound as a white solid (20 mg, 98%).

¹H NMR (500 MHz, CD₃OD): δ 8.80 (d, J=8.1 Hz, 1H), 8.46 (s, 1H), 7.91(d, J=8.1 Hz, 1H), 4.53 (s, 4H), 4.17 (s, 3H).

LCMS (ESI) Rt=2.02 minutes MS m/z 235 [M+H]⁺

The following Preparations were prepared according to Method 13(Preparation 55) or Method 15 (Preparation 126) using the appropriateaniline as described below. The crude reaction residues were purified asdescribed or according to one of the following methods:

-   Method A: Silica gel column chromatography eluting with 0-15% MeOH    in EtOAc.-   Method B: Silica gel column chromatography eluting with 0-60% EtOAc    in cyclohexanes.

Preparation No Name/Structure Data 127

¹H NMR (500 MHz, MeOD): δ 8.47 (d, J = 8.5 Hz, 1H), 8.41 (s, 1H), 7.99(s, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.31 (dd, J = 8.5, 2.0 Hz, 1H), 4.03(s, 3H), 4.00 (s, 3H). LCMS (ESI) Rt = 1.61 minutes MS m/z 233 [M + H]+Using 2-methoxy-4-(1-methyl-1H-1,2,4- triazol-5-yl)aniline (Preparation166). Method 13. 128

¹H NMR (500 MHz, DMSO-d₆): δ 9.63 (s, 1H), 8.28 (d, J = 1.9 Hz, 1H),8.19 (s, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 0.9 Hz, 1H), 7.24(d, J = 1.8 Hz, 1H), 7.12 (dd, J = 8.2, 1.9 Hz, 1H), 4.14 (q, J = 7.3Hz, 2H), 3.91 (s, 3H), 1.41 (t, J = 7.3 Hz, 3H). LCMS (ESI) Rt = 1.99minutes MS m/z 246 [M + H]⁺ Using 4-(1-ethyl-1H-pyrazol-4-yl)-2-methoxyaniline (Preparation 155) and purification method B. Method 13.129

¹H NMR (500 MHz, DMSO-d⁶): δ 9.86 (s, 1H), 8.34 (s, 1H), 8.25 (d, J =8.3 Hz, 1H), 7.25 (d, J = 1.8 Hz, 1H), 7.21 (dd, J = 8.4, 1.8 Hz, 1H),4.46 (br. s, 1H), 4.22 (br. s, 2H), 4.15 (s, 1 3.90 (s, 3H), 3.84 (br.s, 1H), 3.22 (s, 3H). LCMS (ESI) Rt = 1.66 minutes MS m/z 265 [M + H]⁺Using (4-amino-3-methoxyphenyl)(3- methoxyazetidin-1-yl)methanone(Preparation 28) and purification method A. Method 13. 130

¹H NMR (500 MHz, CD₃OD): δ 8.54 (d, J = 8.1 Hz, 1H), 8.38 (s, 1H),7.23-7.25 (m, 2H), 4.08 (s, 3H), 3.95 (s, 3H), 2.44 (s, 3H). LCMS Rt =1.32 minutes MS m/z 247 [M + H]⁺ Using6-(1,2-dimethyl-1H-imidazol-5-yl)-2- methoxypyridin-3-amine (Preparation191). Method 15. 131

¹H NMR (500 MHz, CD₃OD): δ 8.53 (d, J = 8.4 Hz, 1H), 8.42 (s, 1H), 7.48(d, J = 1.9 Hz, 1H), 7.40 (dd, J = 8.4, 1.9 Hz, 1H), 4.23 (s, 4H), 4.02(s, 3H). LCMS (ESI) Rt = 1.72 minutes MS m/z 234 [M + H]⁺ Using2-methoxy-4-(1-methyl-1H-tetrazol- 5-yl)aniline (Preparation 192).Method 15. 132

¹H NMR (500 MHz, CDCl₃): δ 8.56 (d, J = 8.1 Hz, 1H), 8.48 (d, J = 1.7Hz, 1H), 7.70- 7.73 (m, 2H), 7.02 (d, J = 8.1 Hz, 1H), 4.06 (s, 3H),3.88 (s, 3H), 2.57 (s, 3H). LCMS (ESI) Rt = 2.36 minutes [M + H]⁺ Using6-(1,3-dimethyl-1H-pyrazol-4-yl)-2- methoxypyridin-3-amine (Preparation163). Method 15. 133

¹H NMR (500 MHz, CDCl₃): δ 8.57 (d, J = 8.1 Hz, 1H), 8.49 (s, 1H), 7.79(s, 1H), 7.67 (br s, 1H), 7.07 (d, J = 8.1 Hz, 1H), 4.07 (s, 3H), 3.85(s, 3H), 2.65 (s, 3H). LCMS (ESI) Rt = 2.36 minutes MS m/z 247 [M + H]⁺Using 6-(1,5-dimethyl-1H-pyrazol-4-yl)-2- methoxypyridin-3-amine(Preparation 167). Method 15. 134

¹H NMR (500 MHz, CDCl₃): δ 8.73 (d, J = 8.1 Hz, 1H), 8.55 (s, 1H), 7.96(s, 1H), 7.82 (br s, 1H), 7.29 (d, J = 8.1 Hz, 1H), 4.43 (s, 3H), 4.10(s, 3H). LCMS (ESI) Rt = 1.80 minutes MS m/z 234 [M + H]⁺ Using2-methoxy-6-(1-methyl-1H-1,2,3- triazol-5-yl)pyridin-3-amine(Preparation 193). Method 15. 135

¹H NMR (500 MHz, CDCl₃): δ 8.67 (d, J = 8.1 Hz, 1H), 8.52 (s, 1H), 8.04(s, 1H), 7.77 (br s, 1H), 7.53 (d, J = 8.1 Hz, 1H), 4.26 (s, 3H), 4.11(s, 3H). LCMS (ESI) Rt = 2.06 minutes MS m/z 234 [M + H]⁺ Using2-methoxy-6-(2-methyl-2H-1,2,3- triazol-4-yl)pyridin-3-amine(Preparation 194). Method 15. 136

¹H NMR (500 MHz, MeOD): δ 8.31 (s, 1H), 7.95 (s, 1H), 7.81 (s, 1H), 7.65(d, J = 8.5 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.38 (dd, J = 8.5, 2.0Hz, 1H), 3.98 (s, 3H), 2.68 (q, J = 7.5 Hz, 2H), 1.25 (t, J = 7.5 Hz,3H). LCMS (ESI) Rt = 1.87 minutes MS m/z 230 [M + H]⁺ Using2-ethyl-4-(1-methyl-1H-pyrazol-4- yl)aniline (Preparation 168) for 3hours. Method 13. 137

¹H NMR (500 MHz, MeOD): δ 8.35 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.01(s, 1H), 7.84 (d, J = 0.5 Hz, 1H), 7.54 (dd, J = 8.5, 2.0 Hz, 1H), 3.94(s, 3H). LCMS (ESI) Rt = 2.09 minutes MS m/z 286 [M + H]⁺ Using4-(1-methyl-1H-pyrazol-4-yl)-2- (trifluoromethoxy)aniline (Preparation169) for 1 hour. Method 13. 138

¹H NMR (500 MHz, MeOD): δ 8.23 (s, 1H), 7.96 (d, J = 9.0 Hz, 1H), 6.61(d, J = 2.5 Hz, 1H), 6.54 (dd, J = 9.0, 2.5 Hz, 1H), 3.89 (s, 3H),3.76-3.72 (m, 6H), 2.71 (dt, J = 12.5, 2.0 Hz, 2H), 2.63 (app t, J = 5.0Hz, 4H), 2.33 (m, 1H), 2.04 (br d, J = 12.5 Hz, 2H), 1.63 (qd, J = 12.5,3.5 Hz, 2H). LCMS (ESI) Rt = 0.64 minutes MS m/z 320 [M + H]⁺ Using2-methoxy-4-(4- morpholinopiperidin-1-yl)aniline (Preparation 170) for 3hours. Method 13. 139

¹H NMR (500 MHz, MeOD): δ 8.23 (s, 1H), 7.95 (d, J = 9.0 Hz, 1H), 6.65(d, J = 3.0 Hz, 1H), 6.54 (dd, J = 9.0, 3.0 Hz, 1H), 3.89 (s, 3H),3.15-3.12 (m, 4H), 1.73 (quin, J = 6.0 Hz, 4H), 1.63-1.58 (m, 2H). LCMS(ESI) Rt = 0.86 minutes MS m/z 235 [M + H]⁺ Using2-methoxy-4-(piperidin-1-yl)aniline (Preparation 171) for 3 hours.Method 13. 140

¹H NMR (500 MHz, MeOD): δ 8.23 (s, 1H), 7.96 (d, J = 9.0 Hz, 1H), 6.67(d, J = 2.5 Hz, 1H), 6.54 (dd, J = 9.0, 2.5 Hz, 1H), 3.89 (s, 3H),3.73-3.69 (m, 4H), 3.68-3.64 (m, 4H), 3.62-3.59 (m, 2H), 2.81 (m, 1H),2.77 (dd, J = 12.0, 2.5 Hz, 2H), 1.91-1.86 (m, 2H), 1.85-1.81 (m, 2H).LCMS (ESI) Rt = 1.09 minutes MS m/z 348 [M + H]⁺ Using (1-(4-amino-3-methoxyphenyl)piperidin-4- yl)(morpholino)methanone (Preparation 159)for 2 hours. Method 13. 141

¹H NMR (500 MHz, MeOD): δ 8.24 (s, 1H), 7.98 (d, J = 9.0 Hz, 1H), 6.66(d, J = 2.5 Hz, 1H), 6.53 (dd, J = 9.0, 2.5 Hz, 1H), 3.89 (s, 3H), 3.22(t, J = 5.5 Hz, 4H), 2.68 (app t, J = 5.5 Hz, 4H), 2.40 (s, 3H). LCMS(ESI) Rt = 0.50 minutes MS m/z 250 [M + H]⁺ Using2-methoxy-4-(4-methylpiperazin-1- yl)aniline (Preparation 160) for 2hours. Method 13. 142

¹H NMR (500 MHz, MeOD): δ 8.29 (s, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.03(d, J = 3.0 Hz, 1H), 6.93 (dd, J = 9.0, 3.0 Hz, 1H), 3.84-3.81 (m, 4H),3.15-3.13 (m, 4H). LCMS (ESI) Rt = 1.74 minutes MS m/z 241 [M + H]⁺Using 2-chloro-4-morpholinoaniline (Preparation 161). Method 13. 143

¹H NMR (500 MHz, MeOD): δ 8.23 (s, 1H), 8.00 (d, J = 9.0 Hz, 1H), 6.69(d, J = 2.5 Hz, 1H), 6.56 (dd, J = 9.0, 2.5 Hz, 1H), 3.90 (s, 3H),3.38-3.36 (m, 4H), 3.28-3.26 (m, 4H), 2.90 (s, 3H). LCMS (ESI) Rt = 1.57minutes MS m/z 314 [M + H]⁺ Using 2-methoxy-4-(4-(methylsulfonyl)piperazin-1-yl)aniline (Preparation 162). Method 13. 144

¹H NMR (500 MHz, MeOD): δ 8.37 (s, 1H), 8.30 (d, J = 8.5 Hz, 1H), 7.14(d, J = 1.5 Hz, 1H), 7.00 (dd, J = 8.5, 1.5 Hz, 1H), 6.86 (s, 1H), 4.19(t, J = 5.5 Hz, 2H), 3.95 (s, 3H), 3.48 (t, J = 5.5 Hz, 2H), 3.23 (s,3H), 2.46 (s, 3H). LCMS (ESI) Rt = 1.16 minutes MS m/z 290 [M + H]⁺Using 2-methoxy-4-(1-(2-methoxyethyl)-2- methyl-1H-imidazol-5-yl)aniline(Preparation 164) for 1 hour. Method 13. 145

¹H NMR (500 MHz, MeOD): δ 8.34 (s, 1H), 8.25 (d, J = 8.0 Hz, 1H), 7.66(s, 1H), 7.10 (d, J = 2.0 Hz, 1H), 7.00 (dd, J = 8.0, 2.0 Hz, 1H), 3.98(s, 3H), 3.95 (s, 3H). LCMS (ESI) Rt = 1.95 minutes MS m/z 290 [M + H]⁺Using (4-(4-amino-3-methoxyphenyl)-1- methyl-1H-pyrazol-5-yl)methanol(Preparation 165). Method 13. 146

¹H NMR (500 MHz, MeOD): δ 8.37 (s, 1H), 8.32 (d, J = 8.0 Hz, 1H), 7.11(d, J = 2.0 Hz, 1H), 7.02 (dd, J = 8.0, 2.0 Hz, 1H), 3.95 (s, 3H), 3.08(s, 6H). LCMS (ESI) Rt = 1.50 minutes MS m/z 223 [M + H]⁺ Using4-amino-3-methoxy-N,N- dimethylbenzamide (Preparation 24) for 3 hours.Method 13. 147

¹H NMR (500 MHz, MeOD): δ 8.37 (s, 1H), 8.34 (d, J = 8.5 Hz, 1H), 7.10(d, J = 1.5 Hz, 1H), 7.01 (dd, J = 8.5, 1.5 Hz, 1H), 3.96 (s, 3H),3.70-3.67 (m, 2H), 2.51-2.48 (m, 2H), 2.35 (s, 3H). LCMS (ESI) Rt = 0.51minutes MS m/z 278 [M + H]⁺ Using (4-amino-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone (Preparation 211) for 3 hours. Method 13.148

¹H NMR (500 MHz, DMSO-d₆): δ 10.07 (s, 1H), 8.39 (s, 1H), 8.37 (s, 1H),7.52 (d, J = 1.7 Hz, 1H), 7.4 (dd, J = 8.4, 1.8 Hz, 1H), 3.92 (s, 3H).LCMS (ESI) Rt = 1.76 minutes MS m/z 177 [M + H]⁺ Using4-amino-3-methoxybenzonitrile. Method 15. 149

¹H NMR (500 MHz, MeOD): 8.34 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.99 (s,1H), 7.83 (s, 1H), 7.43-7.40 (m, 2H), 3.96 (d, J = 3.5 Hz, 1H), 3.94 (s,3H). LCMS (ESI) Rt = 1.99 minutes MS m/z 268 [M + H]⁺ Using2-(difluoromethoxy)-4-(1-methyl- 1H-pyrazol-4-yl)aniline (Preparation213). Method 13. 150

¹H NMR (500 MHz, Acetone-d6): δ 9.22 (br s, 1H), 8.55 (d, J = 8.5 Hz,1H), 8.52 (s, 1H), 8.36 (s, 1H), 7.41 (d, J = 1.5 Hz, 1H), 7.31 (dd, J =8.5, 1.5 Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H), 3.88 (s, 3H), 1.45 (t, J =7.0 Hz, 3H). LCMS (ESI) Rt = 1.29 minutes MS m/z 247 [M + H]⁺ Using2-ethoxy-4-(4-methyl-4H-1,2,4- triazol-3-yl)aniline (Preparation 216)for 30 minutes. Method 13. 151

¹H NMR (500 MHz, d₆-DMSO): δ 10.01(s, 1H), 8.32 (d, J = 1.5 Hz, 1H),8.24 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 2 Hz, 1H), 7.31 (dd, J = 8.8, 2.2Hz, 1H), 7.14 (t, J = 73 Hz, 1H). LCMS (ESI) Rt = 2.12 minutes MS m/z222 [M + H]⁺ Using 4-chloro-2-(difluoromethoxy)aniline. Method 13. 152

¹H NMR (500 MHz, d₆-DMSO): δ 9.91(s, 1H), 8.29 (d, J = 1.7 Hz, 1H), 8.14(dd, J = 9.1, 6.2 Hz, 1H), 7.27 (t, J = 70 Hz, 1H), 7.21 (dd, J = 9.6,2.8 Hz, 1H), 7.12 (m, 1H). LCMS (ESI) Rt = 2.04 minutes MS m/z 206 [M +H]⁺ Using 2-(difluoromethoxy)-4-fluoroaniline. Method 13. 153

¹H NMR (500 MHz, CDCl₃): δ 8.51 (s, 1H), 8.39 (d, J = 8.9 Hz, 1H), 7.67(s, 1H), 7.42 (s, 1H), 7.24 (d, J = 8.9 Hz, 1H). LCMS (ESI) Rt = 1.84minutes MS m/z 190 [M + H]⁺ Using 2,4-dichloroaniline. Method 13.

Preparation 154N-(2-methoxy-4-(tetrahydro-2H-pyran-4-yl)phenyl)formamide

A solution of 4-(3,6-dihydro-2H-pyran-4-yl)-2-methoxyaniline(Preparation 156, 206 mg, 1.004 mmol) in EtOH (10 mL) was treated withPd/C (10% w/w, 50 mg, 0.047 mmol) and stirred in an atmosphere ofhydrogen for 36 hours. The suspension was filtered over celite andconcentrated in vacuo. The residue was dissolved in formic acid (6 mL)and heated to reflux for 2 hours. The solution was concentrated in vacuoand azeotroped with toluene twice. The residue was purified by silicagel column chromatography eluting with 0 to 30% EtOAc in cyclohexanes togive the title compound (165 mg, 70%).

¹H NMR (500 MHz, DMSO-d₆): δ 9.56 (s, 1H), 8.27 (d, J=1.9 Hz, 1H), 8.04(d, J=8.2 Hz, 1H), 6.94 (d, J=1.8 Hz, 1H), 6.79 (dd, J=8.2, 1.8 Hz, 1H),3.95 (dt, J=11.1, 3.1 Hz, 2H), 3.86 (s, 3H), 3.42 (ddd, J=11.3, 8.6, 5.5Hz, 2H), 2.80-2.67 (m, 1H), 1.78-1.57 (m, 4H).

LCMS (ESI) Rt=2.09 minutes MS m/z 236 [M+H]⁺

The following Preparations were prepared according to Preparation 66using the appropriate halo aniline and boronic acid or ester asdescribed below. The crude reaction residues were purified as describedor according to one of the following methods:

-   Method A: Silica gel column chromatography eluting with-   Method B: Silica gel column chromatography eluting with

Preparation No Name/Structure Data 155

¹H NMR (500 MHz, CDCl₃): δ 7.71 (d, J = 0.9 Hz, 1H), 7.57 (d, J = 0.8Hz, 1H), 6.94 (dd, J = 7.9, 1.8 Hz, 1H), 6.92 (d, J = 1.8 Hz, 1H), 6.74(d, J = 7.9 Hz, 1H), 4.22 (q, J = 7.3 Hz, 2H), 3.92 (s, 3H), 3.80 (br.s, 2H), 1.55 (t, J = 7.3 Hz, 3H). LCMS (ESI) Rt = 1.28 minutes MS m/z218 [M + H]⁺ Using 4-bromo-2-methoxyaniline and 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole. 156

¹H NMR (500 MHz, DMSO-d6): δ 6.89 (d, J = 1.9 Hz, 1H), 6.78 (dd, J =8.1, 1.9 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 6.03 (p, J = 1.6 Hz, 1H),4.77 (s, 2H), 4.19 (q, J = 2.7 Hz, 2H), 3.85-3.73 (m, 5H), 2.42-2.33 (m,2H). LCMS (ESI) Rt = 1.28 minutes MS m/z 206 [M + H]⁺ Using2-(3,6-dihydro-2H-pyran-4-yl)- 4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand 4-bromo-2-methoxyaniline.

Preparation 157 2-Chloro-4-(5-methyl-1,3,4-oxadiazol-2-yl)aniline

To a mixture of 4-(5-methyl-1,3,4-oxadiazol-2-yl)aniline (0.220 g, 1.26mmol) and anhydrous DMF (1.9 mL) was added N-chlorosuccinimide (0.168 g,1.26 mmol). The reaction mixture was heated at 40° C. for 1.5 hoursunder argon before cooling to room temperature and partitioning betweenEtOAc (90 mL) and saturated aqueous NaHCO₃ (15 mL). The organic layerwas washed with saturated aqueous NaHCO₃ (15 mL), dried (Na₂SO₄) andconcentrated in vacuo. The residue was absorbed on silica gel (1.4 g)and purified using silica gel column chromatography eluting with 0-30%EtOAc in DCM to afford the title compound (0.130 g, 49%).

¹H NMR (500 MHz, DMSO-d₆): δ 7.72 (d, J=2.0 Hz, 1H), 7.61 (dd, J=2.0,8.5 Hz, 1H), 6.90 (d, J=8.2 Hz, 1H), 6.14 (s, 2H), 2.53 (s, 3H).

LCMS (ESI) Rt=2.06 minutes MS m/z 210 [M³⁵Cl+H]⁺

Preparation 158 2-Methoxy-6-(1-methyl-1H-tetrazol-5-yl)pyridin-3-amine

10% Pd on carbon (10 mg, 0.411 mmol) was added to a solution of2-methoxy-6-(1-methyl-1H-tetrazol-5-yl)-3-nitropyridine (Preparation189, 97 mg, 0.411 mmol) in EtOH/DCM 2/1 (2.7 mL). The reaction mixturewas stirred at room temperature under a hydrogen atmosphere for 2 hours.The reaction was filtered and the filtrate was concentrated underreduced pressure to afford the title product as a white solid (84 mg,99%).

¹H NMR (500 MHz, CD₃OD): δ 7.67 (d, J=8.0 Hz, 1H); 7.03 (d, J=8.0 Hz,1H), 4.48 (s, 3H), 4.07 (s, 3H).

LCMS (ESI) Rt=2.08 minutes MS m/z 207 [M+H]⁺

Preparation 159(1-(4-amino-3-methoxyphenyl)piperidin-4-yl)(morpholino)methanone

The title compound was prepared according to the method described forPreparation 158 using(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)(morpholino)methanone(Preparation 204) at 30° C.

¹H NMR (500 MHz, MeOD): 6.71 (d, J=9.0 Hz, 1H), 6.63 (d, J=2.5 Hz, 1H),6.48 (dd, J=9.0, 2.5 Hz, 1H), 3.85 (s, 3H), 3.71-3.59 (m, 8H), 3.50 (brd, J=12.5 Hz, 2H), 2.76 (m, 1H), 2.70 (dt, J=12.5, 2.5 Hz, 2H), 1.92(dq, J=12.5, 2.5 Hz, 2H), 1.82 (br d, J=12.5 Hz, 2H).

LCMS (ESI) Rt=0.81 minutes MS m/z 320 [M+H]⁺

Preparation 160 2-methoxy-4-(4-methylpiperazin-1-yl)aniline

The title compound was prepared according to the method described forPreparation 158 using 1-(3-methoxy-4-nitrophenyl)-4-methylpiperazine(Preparation 206).

¹H NMR (500 MHz, MeOD): δ 6.72 (d, J=8.5 Hz, 1H), 6.61 (d, J=2.5 Hz,1H), 6.46 (dd, J=8.5, 2.5 Hz, 1H), 3.85 (s, 3H), 3.08 (br t, J=5.0 Hz,4H), 2.63 (br t, J=5.0 Hz, 4H), 2.36 (s, 3H).

LCMS (ESI) Rt=0.24 minutes MS m/z 222 [M+H]⁺

Preparation 161 2-chloro-4-morpholinoaniline

The title compound was prepared according to the method described forPreparation 158 using 4-(3-chloro-4-nitrophenyl)morpholine (Preparation207). The residue was purified using reverse phase chromatographyeluting with 0-20% MeCN in water.

¹H NMR (500 MHz, MeOD): δ 6.90 (dd, J=2.5, 0.5 Hz, 1H), 6.83-6.79 (m,2H), 3.82-3.80 (m, 4H), 3.00-2.98 (m, 4H).

LCMS (ESI) Rt=1.13 minutes MS m/z 213 [M+H]⁺

Preparation 162 2-methoxy-4-(4-(methylsulfonyl)piperazin-1-yl)aniline

The title compound was prepared according to the method described forPreparation 158 using1-(3-methoxy-4-nitrophenyl)-4-(methylsulfonyl)piperazine (Preparation208).

¹H NMR (500 MHz, MeOD): δ 6.72 (d, J=8.0 Hz, 1H), 6.63 (d, J=2.0 Hz,1H), 6.47 (dd, J=8.0, 2.0 Hz, 1H), 3.86 (s, 3H), 3.37-3.35 (m, 4H),3.14-3.12 (m, 4H), 2.89 (s, 3H).

LCMS (ESI) Rt=0.67 minutes MS m/z 286.31 [M+H]⁺

Preparation 1636-(1,3-Dimethyl-1H-pyrazol-4-yl)-2-methoxypyridin-3-amine

Tetrakis(triphenylphosphine)palladium (0.085 g, 0.074 mmol) was added toa solution of 6-bromo-2-methoxypyridin-3-amine (0.15 g, 0.739 mmol),1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.180 g, 0.813 mmol) and cesium fluoride (0.337 g, 2.216 mmol) inDME/MeOH 2/1 (4.6 mL). The reaction mixture was heated under microwaveirradiation at 150° C. for 10 minutes. The reaction was concentrated invacuo. The residue was purified via Biotage silica gel columnchromatography eluting with DCM/EtOH (99/1 to 90/10, 12 g column) andthen eluted through an SCX-2 column to afford the title product as ayellow solid (120 mg, 74%).

¹H NMR (500 MHz, CD₃OD): δ 7.79 (s, 1H), 6.97 (d, J=7.7 Hz, 1H), 6.90(d, J=7.7 Hz, 1H), 4.00 (s, 3H), 3.82 (s, 3H), 1.50 (s, 3H).

LCMS (ESI) Rt=2.19 minutes MS m/z 219 [M+H]⁺

Preparation 1642-methoxy-4-(1-(2-methoxyethyl)-2-methyl-1H-imidazol-5-yl)aniline

The title compound was prepared according to the method described forPreparation 158 using2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and5-bromo-1-(2-methoxyethyl)-2-methyl-1H-imidazole (Preparation 209).

¹H NMR (500 MHz, MeOD): δ 6.90 (d, J=1.5 Hz, 1H), 6.81 (d, J=8.0 Hz,1H), 6.78 (dd, J=8.0, 1.5 Hz, 1H), 6.75 (s, 1H), 4.13 (t, J=5.5 Hz, 2H),3.88 (s, 3H), 3.45 (t, J=5.5 Hz, 2H), 3.22 (s, 3H), 2.44 (s, 3H).

LCMS (ESI) Rt=1.02 minutes MS m/z 262.27 [M+H]⁺

Preparation 165(4-(4-Amino-3-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl)methanol

The title compound was prepared according to the method described forPreparation 158 using (4-bromo-1-methyl-1H-pyrazol-5-yl)methanol(Preparation 222) and2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Theresidue was purified using Biotage silica gel column chromatographyeluting with EtOAc followed by elution through an SCX-2 cartridge.

Preparation 166 2-methoxy-4-(1-methyl-1H-1,2,4-triazol-5-yl)aniline

The title compound was prepared according to the method described forPreparation 158 using 5-bromo-1-methyl-1H-1,2,4-triazole and2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. Theresidue was purified using Biotage silica gel column chromatographyeluting with EtOAc.

¹H NMR (500 MHz, CDCl₃): δ 7.88 (s, 1H), 7.18 (d, J=1.86 Hz, 1H), 7.04(dd, J=1.86, 8.02 Hz, 1H), 6.76 (d, J=8.02 Hz, 1H), 3.98 (s, 3H), 3.90(s, 3H).

LCMS (ESI) Rt=1.25 minutes MS m/z 205 [M+H]⁺

Preparation 1676-(1,5-Dimethyl-1H-pyrazol-4-yl)-2-methoxypyridin-3-amine

The title compound was prepared according to the method described forPreparation 158 using 6-bromo-2-methoxypyridin-3-amine and1,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.The crude residue was purified using silica gel column chromatographyeluting with 1-10% MeOH/aqueous ammonia (10/1) in DCM.

¹H NMR (500 MHz, CD₃OD): δ 7.69 (s, 1H), 7.00 (d, J=7.7 Hz, 1H), 6.95(d, J=7.7 Hz, 1H), 4.01 (s, 3H), 3.81 (s, 3H), 2.64 (s, 3H).

LCMS (ESI) Rt=2.24 minutes MS m/z 219 [M+H]⁺

Preparation 168 2-ethyl-4-(1-methyl-1H-pyrazol-4-yl)aniline

The title compound was prepared according to the method described forPreparation 98 using 4-bromo-2-ethylaniline and1-methylpyrazole-4-boronic acid pinacol ester.

¹H NMR (500 MHz, MeOD): δ 7.76 (s, 1H), 7.66 (s, 1H), 7.20 (d, J=2.0 Hz,1H), 7.15 (dd, J=8.0, 2.0 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 3.89 (s, 3H),2.57 (q, J=7.5 Hz, 2H), 1.25 (t, J=7.5 Hz, 3H).

LCMS (ESI) Rt=1.24 minutes MS m/z 202 [M+H]⁺

Preparation 169 4-(1-methyl-1H-pyrazol-4-yl)-2-(trifluoromethoxy)aniline

The title compound was prepared according to the method described forPreparation 98 using 2-trifluoromethoxy-4-bromoaniline and1-methylpyrazole-4-boronic acid pinacol ester.

¹H NMR (500 MHz, MeOD): δ 7.82 (s, 1H), 7.69 (s, 1H), 7.28-7.26 (m, 2H),6.87 (d, J=9.0 Hz, 1H), 3.90 (s, 3H).

LCMS (ESI) Rt=2.16 minutes MS m/z 258 [M+H]⁺

Preparation 170 2-methoxy-4-(4-morpholinopiperidin-1-yl)aniline

The title compound was prepared according to the method described forPreparation 79 using4-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)morpholine (Preparation202). The residue was purified using reverse phase chromatographyeluting with 100% water.

¹H NMR (500 MHz, MeOD): δ 6.71 (d, J=8.5 Hz, 1H), 6.63 (d, J=2.5 Hz,1H), 6.48 (dd, J=8.5, 2.5 Hz, 1H), 3.85 (3H, s), 3.73 (t, J=5.0 Hz, 4H),3.53 (br d, J=12.5 Hz, 2H), 2.67-2.62 (m, 6H), 2.31 (m, 1H), 2.03 (br d,J=12.5 Hz, 2H), 1.67 (qd, J=12.5, 4.0 Hz, 2H).

LCMS (ESI) Rt=0.25 minutes MS m/z not observed.

Preparation 171 2-methoxy-4-(piperidin-1-yl)aniline

The title compound was prepared according to the method described forPreparation 79 using 1-(3-methoxy-4-nitrophenyl)piperidine (Preparation203). The residue was purified using reverse phase chromatographyeluting with 100% water.

¹H NMR (500 MHz, MeOD): δ 6.71 (d, J=8.5 Hz, 1H), 6.63 (s, 1H), 6.49 (d,J=8.5 Hz, 1H), 3.85 (s, 3H), 2.99 (app br s, 4H), 1.75 (quin, J=5.5 Hz,4H), 1.60-1.54 (m, 2H).

LCMS (ESI) Rt=0.55 minutes MS m/z 207 [M+H]⁺

Preparation 172N-(2-methoxy-2-methylpropyl)-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-amine

To a cooled (0° C.) solution ofN-(2-methoxy-2-methylpropyl)-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8-amine(Preparation 175, 63 mg, 0.215 mmol) in DCM (10 mL) was added mCPBA (116mg, 0.517 mmol). The reaction mixture was stirred for 18 hours, whilstslowly warming to room temperature. Further mCPBA (50 mg, 0.223 mmol)was added and the reaction mixture stirred at room temperature for afurther 2 hours. The reaction mixture was diluted with DCM (30 mL),washed with saturated aqueous NaHCO₃ (30 mL), brine (30 mL), dried(MgSO₄) and concentrated in vacuo. The residue was purified by silicagel column chromatography eluting with 50-100% EtOAc in cyclohexanes toafford the title compound (29 mg, 41%).

¹H NMR (500 MHz, MeOD): δ 9.41 (s, 1H), 6.94 (d, J=0.5 Hz, 1H), 3.76 (s,2H), 3.46 (s, 3H), 3.33 (s, 3H), 2.53 (d, J=0.5 Hz, 3H), 1.29 (s, 6H).

LCMS (ESI) Rt=1.94 minutes MS m/z 325 [M+H]⁺

Preparation 173N-(2-Methoxy-2-methylpropyl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-amine

N-(2-Methoxy-2-methylpropyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-amine(Preparation 176, 220 mg, 0.79 mmol) was dissolved in dichloromethane(10 mL). To the stirred solution was added portionwise3-chlorobenzoperoxoic acid (75%, 370 mg, 1.58 mmol). After 1 hour, ethylacetate was added (50 mL) and the organic solution was washed withsaturated sodium bicarbonate (20 mL), brine (20 mL), dried andconcentrated in vacuo. The crude was purified by silica gel columnchromatography eluting with 20% hexane in ethyl acetate to afford thetitle compound as a yellow powder (180 mg, 73%).

¹H NMR (500 MHz, CDCl₃): δ 9.37 (s, 1H), 8.25 (d, J=5.8 Hz, 1H), 7.15(br s, 1H), 6.93 (d, J=5.8 Hz, 1H), 3.71 (d, J=5.7 Hz, 2H), 3.44 (s,3H), 3.29 (s, 3H), 1.28 (s, 6H).

LCMS (ESI) Rt=1.68 minutes MS m/z 311 [M+H]⁺

Preparation 1742-(methylsulfonyl)-N-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidin-8-amine

The title compound was prepared according to the method described forPreparation 172 usingN-((3-methyltetrahydrofuran-3-yl)methyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-amine(Preparation 177). The residue was purified using silica gel columnchromatography eluting with 0-3% MeOH in EtOAc.

¹H NMR (500 MHz, MeOD): δ 9.54 (s, 1H), 8.23 (d, J=5.5 Hz, 1H), 7.09 (d,J=5.5 Hz, 1H), 3.99 (td, J=8.5, 6.5 Hz, 1H), 3.90 (td, J=8.5, 6.5 Hz,1H), 3.84 (d, J=8.5 Hz, 1H), 3.77 (d, J=13.5 Hz, 1H), 3.71 (d, J=13.5Hz, 1H), 3.49 (s, 3H), 3.47 (d, J=8.5 Hz, 1H), 2.06 (m, 1H), 1.75 (m,1H), 1.24 (s, 3H).

LCMS (ESI) Rt=1.75 minutes MS m/z 323 [M+H]⁺

Preparation 175N-(2-methoxy-2-methylpropyl)-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8-amine

To a solution of 8-chloro-6-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine(Preparation 52, 80 mg, 0.354 mmol) in NMP (7 mL) was added2-methoxy-2-methylpropan-1-amine (0.086 ml, 0.709 mmol) andtriethylamine (0.249 mL, 1.772 mmol). The reaction mixture was heated to120° C. for 18 hours. The reaction mixture was diluted with EtOAc (30mL), washed with water (30 mL), dried (MgSO₄) and concentrated in vacuo.The residue was purified by silica gel column chromatography elutingwith 0-50% EtOAc in cyclohexane to afford the title compound (63 mg,61%).

¹H NMR (500 MHz, MeOD): δ 9.03 (s, 1H), 6.75 (d, J=0.5 Hz, 1H), 3.66 (s,2H), 3.32 (s, 3H), 2.65 (s, 3H), 2.45 (d, J=0.5 Hz, 3H), 1.29 (s, 6H).

LCMS (ESI) Rt=2.10 minutes MS m/z 293 [M+H]⁺

Preparation 176N-(2-Methoxy-2-methylpropyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-amine

The title compound was prepared according to the method described forPreparation 175 using 2-methoxy-2-methylpropan-1-amine and8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine (Preparation 33). Theresidue was purified by elution through an SCX-2 column using 50%methanol in chloroform followed by 50% chloroform in 7N NH₃/MeOHfollowed by silica gel column chromatography eluting with EtOAc.

¹H NMR (500 MHz, CDCl₃): δ 8.99 (s, 1H), 7.97 (d, J=5.8 Hz, 1H), 6.95(br s, 1H), 6.75 (d, J=5.8 Hz, 1H), 3.63 (d, J=5.5 Hz, 1H), 3.29 (s,3H), 2.64 (s, 3H), 1.28 (s, 6H).

LCMS (ESI) Rt=2.01 minutes MS m/z 279 [M+H]⁺

Preparation 177N-((3-methyltetrahydrofuran-3-yl)methyl)-2-(methylthio)pyrido[3,4-d]pyrimidin-8-amine

The title compound was prepared according to the method described forPreparation 175 using of 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine(Preparation 33) and (3-methyltetrahydrofuran-3-yl)methanamine at 130°C.

¹H NMR (500 MHz, MeOD): δ 9.13 (s, 1H), 7.92 (d, J=6.0 Hz, 1H), 6.93 (d,J=6.0 Hz, 1H), 4.01 (dt, J=8.5, 5.5 Hz, 1H), 3.89 (dt, J=8.5, 7.0 Hz,1H), 3.84 (d, J=8.5 Hz, 1H), 3.65 (q, J=13.0 Hz, 2H), 3.48 (d, J=8.5 Hz,1H), 2.68 (s, 3H), 2.04 (m, 1H), 1.78 (m, 1H), 1.25 (s, 3H).

LCMS (ESI) Rt=1.89 minutes MS m/z 291 [M+H]⁺

Preparation 1788-chloro-6-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine

The title compound was prepared according to the method described forPreparation 172 using8-chloro-6-methyl-2-(methythio)pyrido[3,4-d]pyrimidine (Preparation 52).The residue was purified using silica gel column chromatography elutingwith 0-100% EtOAc in cyclohexanes.

¹H NMR (500 MHz, acetone-d6): δ 9.91 (s, 1H), 8.07 (d, J=1.0 Hz, 1H),3.52 (s, 3H), 2.77 (d, J=1.0 Hz, 3H).

LCMS (ESI) Rt=1.52 minutes MS m/z 258 [M+H]⁺

Preparation 1798-Chloro-6-cyclopropyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine

The title compound was prepared according to the method described forPreparation 172 using8-Chloro-6-cyclopropyl-2-(methylthio)pyrido[3,4-d]pyrimidine(Preparation 180). The residue was purified using preparative TLCeluting with 2:3 EtOAc:DCM.

¹H NMR (500 MHz, acetone-d₆): δ 8.10 (s, 1H), 3.50 (s, 3H), 2.42 (m,1H), 1.13-1.22 (m, 4H).

Preparation 1808-Chloro-6-cyclopropyl-2-(methylthio)pyrido[3,4-d]pyrimidine

6-Cyclopropyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one(Preparation 181, 180 mg 0.77 mmole) was stirred with phosphorusoxychloride (6 mL) and the reaction was heated at 70° C. for 2 hoursbefore concentrating in vacuo. Ethyl acetate (20 mL) was added to theresidue and the solution was cooled in ice. A little ice and then sodiumbicarbonate solution (10 mL) was added. The mixture was shakenthoroughly and the aqueous layer separated. The organic layer was washedwith sodium bicarbonate solution (10 mL), brine (5 mL), dried andconcentrated in vacuo. The residue was purified using preparative TLCeluting with 1:3 ethyl acetate:cyclohexane to afford the title compound(171 mg 88%).

¹H NMR (500 MHz, CDCl₃): δ 9.13 (s, 1H), 7.40 (s, 1H), 2.73 (s, 3H),2.17 (m, 1H), 1.14 (m, 2H), 1.09 (m, 2H).

Preparation 1816-Cyclopropyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one

5-(Cyclopropylethynyl)-2-(methylthio)pyrimidine-4-carboxylic acid(Preparation 182, 215 mg 0.92 mmole) was dissolved in deuteriochloroform(4.3 mL) and camphor-10-sulphonic acid (22 mg 0.092 mmole) was added.The reaction was heated at 60° C. for 18 hours. The solution wasconcentrated in vacuo and the residue dissolved in 7M ammonia inmethanol (4.5 mL). The reaction was heated to 80° C. under microwaveirradiation for 7.5 hours. The reaction was cooled and concentrated invacuo. The residue was taken up in chloroform (20 mL) and the solutionwas washed with 10% sodium carbonate solution (5 mL) and with water (5mL). The solution was filtered and concentrated in vacuo. The residuewas purified by preparative TLC eluting with EtOAc to afford the titlecompound (95 mg, 44%).

¹H NMR (500 MHz, CDCl₃): δ 8.78 (s, 1H), 6.27 (s, 1H), 2.68 (s, 3H),1.82-1.89 (m, 1H), 0.96-1.05 (m, 4H).

Preparation 1825-(Cyclopropylethynyl)-2-(methylthio)pyrimidine-4-carboxylic acid

Methyl 5-(cyclopropylethynyl)-2-(methylthio)pyrimidine-4-carboxylate(Preparation 183, 520 mg 2.1 mmole) was dissolved in methanol (8 mL) and2M sodium hydroxide (1.6 mL, 3.2 mmole) was added. The reaction wasstirred at room temperature for 3 hours. The reaction was cooled in iceand 2M hydrochloric acid (1.6 mL) was added. The deposited solid wasfiltered, washed with water and dried to afford the title compound (387mg, 78%).

¹H NMR (500 MHz, CDCl₃): δ 8.75 (s, 1H), 2.63 (s, 3H), 1.55-1.61 (m,1H), 0.95-1.02 (m, 4H).

Preparation 183 Methyl5-(cyclopropylethynyl)-2-(methylthio)pyrimidine-4-carboxylate

Methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate (639 mg, 2.43mmole) was dissolved in DMF (6 mL) and triethylamine (1.37 mL) wasadded. To the solution was added ethynylcyclopropane (287 uL, 3.40mmole), followed by copper (I) iodide (22.4 mg 0.115 mmole) andbis(triphenylphosphine)palladium dichloride (85.4 mg 0.115 mmole). Thereaction was placed under nitrogen at heated at 80° C. for 3.25 hours.The reaction was diluted with ethyl acetate (75 mL) and the solution waswashed with water (25 mL). The organic layer was washed again with water(2×25 mL), brine, dried and concentrated in vacuo. The residue waspurified by silica gel column chromatography eluting with 5-10% ethylacetate in cyclohexanes to afford the title compound (520 mg, 86%).Taken on directly to the next step.

Preparation 1848-chloro-5-methyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine

A suspension of 8-chloro-5-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine(Preparation 185, 53 mg, 0.235 mmol) in DCM (2.5 mL) was treated withmCPBA (77% w/w, 150 mg, 0.668 mmol) at 0° C. and then allowed to reachroom temperature for 18 hours. The mixture was quenched with water andextracted with DCM. The combined organic layers were washed with waterand saturated aqueous NaHCO₃, dried and concentrated in vacuo. Theresidue was purified by silica gel column chromatography eluting with60% EtOAc in cyclohexanes to give the title compound (44 mg, 72%).

¹H NMR (500 MHz, DMSO-d₆): δ 10.19 (s, 1H), 8.63 (d, J=1.0 Hz, 1H), 3.56(s, 3H), 2.78 (d, J=1.1 Hz, 3H).

LCMS (ESI) Rt=1.60 minutes MS m/z 258 [M+H]⁺

Preparation 185 8-chloro-5-methyl-2-(methylthio)pyrido[3,4-d]pyrimidine

A solution of 5-methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one(Preparation 186, 48 mg, 0.232 mmol) in POCl₃ (1.5 mL) was heated to 70°C. for 2 hours. The reaction was concentrated in vacuo and partitionedbetween EtOAc and saturated aqueous NaHCO₃. The aqueous layer wasextracted with EtOAc and the combined organic layers were washed withwater and brine, dried and adsorbed on silica. The residue was purifiedby silica gel column chromatography eluting with 0 to 15% EtOAc incyclohexanes to give the title compound (27 mg, 52%).

¹H NMR (500 MHz, CDCl₃): δ 9.38 (s, 1H), 8.23 (d, J=1.1 Hz, 1H), 2.77(s, 3H), 2.68 (d, J=1.0 Hz, 3H).

LCMS (ESI) Rt=2.70 minutes MS m/z 226 [M+H]⁺

Preparation 186 5-methyl-2-(methylthio)pyrido[3,4-d]pyrimidin-8(7H)-one

A solution of N-allyl-5-bromo-2-(methylthio)pyrimidine-4-carboxamide(Preparation 187, 24 mg, 0.083 mmol), diisopropylethyl amine (60 μl,0.344 mmol) and PdCl₂dppf.DCM (7 mg, 8.57 μmol) was dissolved in DMA(0.8 mL) and heated to 120° C. for 18 hours. Additional batches of base(60 uL) and catalyst (7 mg) were added and the mixture stirred at 150°C. for 8 hours. The mixture was diluted with DCM and quenched withbrine. The aqueous layer was extracted with DCM and the combined organiclayers washed with water, dried and concentrated in vacuo. The residuewas purified by silica gel column chromatography eluting with 0 to 5%MeOH in DCM to give the title compound (8 mg, 47%).

¹H NMR (500 MHz, DMSO-d₆): δ 11.68 (br. s, 1H), 9.21 (s, 1H), 7.07 (dd,J=5.7, 1.2 Hz, 1H), 2.61 (s, 3H), 2.25 (d, J=1.2 Hz, 3H).

LCMS (ESI) Rt=1.74 minutes MS m/z 208 [M+H]⁺

Preparation 187 N-allyl-5-bromo-2-(methylthio)pyrimidine-4-carboxamide

A solution of methyl 5-bromo-2-(methylthio)pyrimidine-4-carboxylate(Preparation 30, 1.00 g, 3.80 mmol) was dissolved in methanol (16 mL),treated with allylamine (3.00 mL, 40.0 mmol) and heated to 90° C. for 18hours. The mixture was concentrated in vacuo and the residue purified bysilica gel column chromatography eluting with 0 to 5% EtOAc incyclohexanes to give the title compound (981 mg, 90%).

¹H NMR (500 MHz, CDCl₃) δ 8.79 (s, 1H), 7.73 (br. s, 1H), 5.94 (ddt,J=17.2, 10.2, 5.6 Hz, 1H), 5.31 (dq, J=17.1, 1.6 Hz, 1H), 5.23 (dq,J=10.3, 1.4 Hz, 1H), 4.09 (tt, J=5.9, 1.6 Hz, 2H), 2.60 (s, 3H).

LCMS (ESI) Rt=2.18 minutes MS m/z 289 [M+H]⁺

Preparation 188 6-Methoxy-N-methyl-5-nitropicolinamide

HATU (0.606 g, 1.594 mmol) was added to a solution of6-methoxy-5-nitropicolinic acid (Preparation 190, 0.243 g, 1.226 mmol),DIPEA (0.320 mL, 1.840 mmol) and 2M methylamine solution in THF (1.2 mL,2.453 mmol) in THF (3.3 mL). The reaction mixture was stirred at roomtemperature for 3 hours. Further methylamine (0.6 mL) was added and themixture was stirred for 18 hours. The reaction was quenched with waterand concentrated in vacuo. The aqueous phase was extracted with EtOAc(×2) and the combined organic layers were washed twice with water, dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby Biotage silica gel column chromatography eluting with DCM/EtOAc 99/1to 90/10 to afford the title compound as a yellow solid (182 mg, 70%).

¹H NMR (500 MHz, CDCl₃): δ 8.40 (d, J=8.0 Hz, 1H), 7.96 (d, J=8.0 Hz,1H), 7.64 (br s, 1H), 4.18 (s, 3H), 3.09 (d, J=5.1 Hz, 3H).

LCMS (ESI) Rt=2.06 minutes MS m/z 212 [M+H]⁺

Preparation 189 2-Methoxy-6-(1-methyl-1H-tetrazol-5-yl)-3-nitropyridine

Triflic anhydride (0.29 mL, 1.724 mmol) was added dropwise to a solutionof 6-methoxy-N-methyl-5-nitropicolinamide (Preparation 188, 0.182 g,0.862 mmol) and sodium azide (0.224 g, 3.45 mmol) in MeCN (4.3 mL) at−10° C. The reaction mixture was warmed to room temperature over 3hours. The reaction mixture was neutralised with saturated aqueousNaHCO₃. The mixture was extracted with EtOAc and the organic layerwashed with saturated aqueous NaHCO₃ and then with brine, dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby Biotage silica gel column chromatography eluting withcyclohexane/EtOAc 70/30 to 50/50 to afford the title compound as a whitesolid (99 mg, 49%).

¹H NMR (500 MHz, CDCl₃):δ 8.48 (d, J=8.2 Hz, 1H), 8.15 (d, J=8.2 Hz,1H), 4.56 (s, 3H), 4.22 (s, 3H).

LCMS (ESI) Rt=2.15 minutes MS m/z 237 [M+H]⁺

Preparation 190 6-Methoxy-5-nitropicolinic acid

Chromium trioxide (519 mg, 5.19 mmol) was added to a solution of2-methoxy-6-methyl-3-nitropyridine (300 mg, 1.731 mmol) in sulfuric acid(1.7 mL). The reaction mixture was stirred at room temperature for 20hours. The mixture was poured onto ice/water (15 mL). The solid wascollected and washed with cold water. The aqueous layer was thenextracted with EtOAc. The combined organic layers were dried (Na₂SO₄),filtered and concentrated in vacuo. The solids obtained were combinedand purified by Biotage silica gel column chromatography eluting with 1%formic acid in DCM/EtOAc, 90/10 to 70/30 to afford the title product asa white solid (254 mg, 74%).

¹H NMR (500 MHz, Acetone-d₆): δ 8.56 (d, J=8.0 Hz, 1H), 7.95 (d, J=8.0Hz, 1H), 4.19 (s, 3H).

LCMS (ESI) Rt=1.96 minutes MS m/z 199 [M+H]⁺

Preparation 1916-(1,2-Dimethyl-1H-imidazol-5-yl)-2-methoxypyridin-3-amine

Palladium acetate (5.5 mg, 0.025 mmol) was added to a solution of6-bromo-2-methoxypyridin-3-amine (25 mg, 0.123 mmol),1,2-dimethyl-1H-imidazole (35.5 mg, 0.369 mmol), pivalic acid (3.8 mg,0.037 mmol), tricyclohexylphosphine tetrafluoroborate salt (18.1 mg,0.049 mmol) and potassium carbonate (25.5 mg, 0.185 mmol) in DMA (410μL). The reaction mixture was heated under microwave irradiation at 120°C. for 1 hour. The reaction was diluted with EtOAc and quenched withwater. The layers were separated and the aqueous layer was extractedwith EtOAc. The combined organic layers were dried (Na₂SO₄), filteredand concentrated in vacuo. The crude mixture was purified by Biotagesilica gel column chromatography eluting with 1 to 5% MeOH/aq. NH₃(10/1) in DCM to afford the title compound as a white solid (9 mg, 35%).

¹H NMR (500 MHz, CDCl₃): δ 7.12 (s, 1H), 6.99 (d, J=7.7 Hz, 1H), 6.92(d, J=7.7 Hz, 1H), 4.02 (s, 3H), 3.86 (s, 3H), 3.82 (br s, 2H), 2.44 (s,3H).

LCMS (ESI) Rt=1.09 minutes MS m/z 219 [M+H]⁺

Preparation 192 2-Methoxy-4-(1-methyl-1H-tetrazol-5-yl)aniline

10% Pd on carbon (7 mg, 0.268 mmol) was added to a solution of5-(3-methoxy-4-nitrophenyl)-1-methyl-1H-tetrazole (Preparation 195, 63mg, 0.268 mmol) in EtOAc (1.2 mL). The reaction mixture was stirred atroom temperature under a hydrogen atmosphere for 1 hour. EtOH (0.5 mL)was added and the reaction mixture was stirred for 1.5 hours. Thereaction was filtered and the filtrate concentrated in vacuo to affordthe title product as a white solid (52 mg, 95%).

¹H NMR (500 MHz, CD₃OD): δ 7.25-7.26 (m, 1H), 7.20-7.22 (m, 1H),6.86-6.88 (m, 1H), 4.19 (s, 3H), 3.93 (s, 3H).

LCMS (ESI) Rt=1.54 minutes MS m/z 206 [M+H]⁺

Preparation 1932-Methoxy-6-(1-methyl-1H-1,2,3-triazol-5-yl)pyridin-3-amine

The title compound was prepared according to the method described forPreparation 192 using2-methoxy-6-(1-methyl-1H-1,2,3-triazol-5-yl)-3-nitropyridine(Preparation 197) at 35° C. for 18 hours. The residue was purified usingsilica gel column chromatography eluting with 1-10% EtOAc in DCM.

¹H NMR (500 MHz, CDCl₃): δ 7.84 (s, 1H), 7.11 (d, J=7.8 Hz, 1H), 6.96(d, J=7.8 Hz, 1H), 4.40 (s, 3H), 4.05 (s, 5H).

LCMS (ESI) Rt=1.98 minutes MS m/z 206 [M+H]⁺

Preparation 1942-Methoxy-6-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-3-amine

The title compound was prepared according to the method described forPreparation 192 using2-methoxy-6-(2-methyl-2H-1,2,3-triazol-4-yl)-3-nitropyridine(Preparation 198) for 36 hours.

¹H NMR (500 MHz, CDCl₃): δ 7.97 (s, 1H), 7.34 (d, J=7.7 Hz, 1H), 6.93(d, J=7.7 Hz, 1H), 4.23 (s, 3H), 4.07 (s, 3H), 3.89 (br s, 3H).

LCMS (ESI) Rt=2.11 minutes MS m/z 206 [M+H]⁺

Preparation 195 5-(3-Methoxy-4-nitrophenyl)-1-methyl-1H-tetrazole

Triflic anhydride (0.27 mL, 1.580 mmol) was added dropwise to a solutionof 3-methoxy-N-methyl-4-nitrobenzamide (Preparation 196, 0.166 g, 0.790mmol) and sodium azide (0.205 g, 3.16 mmol) in MeCN (4.0 mL) at −10° C.The reaction mixture was warmed up to room temperature over 3 hours. Thereaction was neutralised with saturated aqueous NaHCO₃. The mixture wasextracted with EtOAc and the organic layer washed with saturated aqueousNaHCO₃, brine, dried (Na₂SO₄), filtered and concentrated in vacuo. Theresidue was purified by Biotage silica gel column chromatography elutingwith cyclohexane/EtOAc 70/30 to 50/50 to afford the title compound as awhite solid (129 mg, 69%).

¹H NMR (500 MHz, CDCl₃): δ 8.04 (d, J=8.3 Hz, 1H), 7.64 (d, J=1.7 Hz,1H), 7.35 (dd, J=8.3, 1.7 Hz, 1H), 4.27 (s, 3H), 4.08 (s, 3H).

LCMS (ESI) Rt=1.98 minutes MS m/z 236 [M+H]⁺

Preparation 196 3-Methoxy-N-methyl-4-nitrobenzamide

HATU (0.501 g, 1.319 mmol) was added to a solution of3-methoxy-4-nitrobenzoic acid (0.2 g, 1.014 mmol), DIPEA (0.265 mL,1.522 mmol) and 2M methylamine solution in THF (1.0 mL, 2.029 mmol) inTHF (2.7 mL). The reaction mixture was stirred at room temperature for18 hours. The reaction was concentrated in vacuo and purified by Biotagesilica gel column chromatography eluting with DCM/EtOAc 80/20 to 60/40followed by a second chromatography eluting with cyclohexane/EtOAc 50/50to 40/60 to afford the title compound as a white solid (166 mg, 78%).

¹H NMR (500 MHz, CDCl₃): δ 7.88 (d, J=8.3 Hz, 1H), 7.64 (d, J=1.6 Hz,1H), 7.28 (dd, J=8.3, 1.6 Hz, 1H), 6.27 (s, 1H), 4.04 (s, 3H), 3.07 (d,J=4.9 Hz, 3H).

LCMS (ESI) Rt=2.04 minutes MS m/z 211 [M+H]⁺

Preparation 1972-Methoxy-6-(1-methyl-1H-1,2,3-triazol-5-yl)-3-nitropyridine

1-Methyl-1H-1,2,3-triazole (0.044 g, 0.530 mmol) was dissolved in THF(5.3 mL) and cooled to −78° C. n-Butyllithium solution in hexanes (0.25mL, 0.636 mmol) was added dropwise and the solution was stirred forfurther 5 minutes before zinc chloride (3.18 mL, 1.591 mmol) was added.After 30 minutes at −78° C., the reaction mixture was diluted with DMF(2.1 mL), tetrakis(triphenylphosphine)palladium(0) (0.031 g, 0.027 mmol)and a solution of 6-chloro-2-methoxy-3-nitropyridine (0.1 g, 0.530 mmol)in DMF (0.53 mL) were added. The solution was stirred at 80° C. for 4hours. After the mixture was cooled to room temperature, H₂O and EtOAcwere added and the phases were separated. The organic phase was washedwith H₂O, brine, dried (Na₂SO₄), filtered and the solvent was removed invacuo. The residue was purified via Biotage silica gel columnchromatography eluting with cyclohexane/EtOAc (99/1 to 50/50) to affordthe title compound as a light yellow solid (51 mg, 41%).

¹H NMR (500 MHz, CDCl₃): δ 8.44 (d, J=8.2 Hz, 1H), 8.15 (s, 1H), 7.43(d, J=8.2 Hz, 1H), 4.50 (s, 3H), 4.21 (s, 3H).

LCMS Rt=2.26 minutes MS m/z 236 [M+H]⁺

Preparation 1982-Methoxy-6-(2-methyl-2H-1,2,3-triazol-4-yl)-3-nitropyridine

Iodomethane (330 μL, 5.31 mmol) was added to a solution of2-methoxy-3-nitro-6-(2H-1,2,3-triazol-4-yl)pyridine (Preparation 199,235 mg, 1.063 mmol) and potassium carbonate (294 mg, 2.125 mmol) in THF(5.1 mL). The reaction mixture was stirred at room temperature for 72hours. The solid was filtered and the filtrate concentrated in vacuo.The residue was purified using Biotage silica gel column chromatographyeluting with cyclohexane/EtOAc 80/20 to 40/60 to afford the titlecompound as a beige solid (48 mg, 19%).

¹H NMR (500 MHz, CDCl₃): δ 8.40 (d, J=8.2 Hz, 1H), 8.17 (s, 1H), 7.66(d, J=8.2 Hz, 1H), 4.31 (s, 3H), 4.22 (s, 3H).

LCMS (ESI) Rt=2.97 minutes MS m/z 236 [M+H]⁺

Preparation 199 2-Methoxy-3-nitro-6-(2H-1,2,3-triazol-4-yl)pyridine

Trimethylsilylazide (1.2 mL, 9.21 mmol) was added to a solution of6-ethynyl-2-methoxy-3-nitropyridine (Preparation 200, 0.082 g, 0.460mmol) in toluene (10.2 mL). The reaction mixture was stirred at 130° C.for 48 hours. The reaction was diluted with water and concentrated invacuo. The residue was purified using Biotage silica gel columnchromatography eluting with cyclohexane/EtOAc 70/30 to 50/50 to affordthe title compound as a beige solid (235 mg, 77%).

¹H NMR (500 MHz, CD₃OD): δ 8.44-8.46 (m, 2H), 7.77 (d, J=8.2 Hz, 1H),4.19 (s, 3H).

LCMS (ESI) Rt=2.47 minutes MS m/z 222 [M+H]⁺

Preparation 200 6-Ethynyl-2-methoxy-3-nitropyridine

Potassium carbonate (0.020 g, 0.148 mmol) was added to a solution of2-methoxy-3-nitro-6-((trimethylsilyl)ethynyl)pyridine (Preparation 201,0.37 g, 1.478 mmol) in MeOH (3 mL). The reaction mixture was stirred atroom temperature for 1 hour. The reaction was concentrated in vacuo anddiluted with EtOAc. The solution was washed with water and the organiclayer was dried (Na₂SO₄) and concentrated in vacuo to afford the titlecompound as a brown solid (248 mg, 94%).

¹H NMR (500 MHz, CDCl₃): δ 8.24 (d, J=8.1 Hz, 1H), 7.20 (d, J=8.1 Hz,1H), 4.12 (s, 3H), 3.37 (s, 1H).

LCMS (ESI) Rt=2.56 minutes MS m/z 179 [M+H]⁺

Preparation 201 2-Methoxy-3-nitro-6-((trimethylsilyl)ethynyl)pyridine

Bis(triphenylphosphine)palladiumdichloride (0.082 g, 0.118 mmol) wasadded to a solution of 6-chloro-2-methoxy-3-nitropyridine (0.554 g, 2.94mmol), trimethylsilylacetylene (0.623 mL, 4.41 mmol), triethylamine(1.843 mL, 13.22 mmol) and copper iodide (0.022 g, 0.118 mmol) in DMF(10.1 mL). The reaction mixture was heated at 80° C. for 1 hour. Thereaction mixture was diluted with water and the aqueous layer wasextracted with EtOAc. The combined organic layers were dried overNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified by Biotage silica gel column chromatography eluting withcyclohexane/EtOAc (99/1) to afford the title compound as a yellow oil(370 mg, 50%).

¹H NMR (500 MHz, CDCl₃): δ 8.24 (d, J=8.1 Hz, 1H), 7.17 (d, J=8.1 Hz,1H), 4.15 (s, 3H), 0.31 (s, 9H).

LCMS (ESI) Rt=3.25 minutes MS m/z 251 [M+H]⁺

Preparation 202 4-(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)morpholine

The title compound was prepared according to the method described forPreparation 78 using 4-fluoro-2-methoxy-1-nitrobenzene and4-(piperidin-4-yl)morpholine. The residue was purified using silica gelcolumn chromatography eluting with 80-100% DCM in cyclohexanes.

¹H NMR (500 MHz, MeOD): δ 7.95 (d, J=9.5 Hz, 1H), 6.57 (dd, J=9.5, 2.5Hz, 1H), 6.52 (d, J=2.5 Hz, 1H), 4.10 (br d, J=13.0 Hz, 2H), 3.95 (s,3H), 3.72 (t, J=5.0 Hz, 4H), 2.99 (td, J=13.0, 2.5 Hz, 2H), 2.62 (t,J=5.0 Hz, 4H), 2.49 (m, 1H), 2.04 (d, J=13.0 Hz, 2H), 1.58 (dd, J=13.0,5.0 Hz, 1H), 1.53 (dd, J=13.0, 5.0 Hz, 1H).

LCMS (ESI) Rt=1.03 minutes MS m/z 322 [M+H]⁺

Preparation 203 1-(3-methoxy-4-nitrophenyl)piperidine

The title compound was prepared according to the method described forPreparation 78 using 4-fluoro-2-methoxy-1-nitrobenzene and piperidine.The residue was purified using silica gel column chromatography elutingwith 50-80% DCM in cyclohexanes.

¹H NMR (500 MHz, CDCl₃): 8.02 (d, J=9.5 Hz, 1H), 6.46 (dd, J=9.5, 3.0Hz, 1H), 6.41 (m, 1H), 3.97 (s, 3H), 3.45-3.42 (m, 4H), 1.76-1.70 (m,6H).

LCMS (ESI) Rt=2.46 minutes MS m/z 237 [M+H]⁺

Preparation 204(1-(3-methoxy-4-nitrophenyl)piperidin-4-yl)(morpholino)methanone

To a solution of 1-(3-methoxy-4-nitrophenyl)piperidine-4-carboxylic acid(Preparation 205, 150 mg, 0.535 mmol) in DMF (5 mL) was added morpholine(0.07 mL, 0.803 mmol), DIPEA (0.19 mL, 1.070 mmol) and HATU (244 mg,0.642 mmol). The reaction mixture was stirred at room temperature for 18hours. The reaction mixture was diluted with water (30 mL) and EtOAc (30ml), dried (MgSO₄) and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluting with 0-10% MeOH in EtOAc toafford the title compound (166 mg, 89%).

¹H NMR (500 MHz, MeOD): δ 7.96 (d, J=9.5 Hz, 1H), 6.58 (dd, J=9.5, 2.5Hz, 1H), 6.52 (d, J=2.5 Hz, 1H), 4.11-4.06 (m, 2H), 3.95 (s, 3H),3.72-3.69 (m, 2H), 3.68-3.65 (m, 4H), 3.61-3.58 (m, 2H), 3.11-3.05 (m,2H), 3.01 (m, 1H), 1.85-1.78 (m, 4H).

LCMS (ESI) Rt=1.90 minutes MS m/z 350 [M+H]⁺

Preparation 205 1-(3-methoxy-4-nitrophenyl)piperidine-4-carboxylic acid

The title compound was prepared according to the method described forPreparation 78 using 4-fluoro-2-methoxy-1-nitrobenzene andpiperidine-4-carboxylic acid.

¹H NMR (500 MHz, MeOD): δ 7.95 (d, J=9.5 Hz, 1H), 6.57 (dd, J=9.5, 2.5Hz, 1H), 6.52 (d, J=2.5 Hz, 1H), 3.98 (dt, J=13.5, 3.5 Hz, 2H), 3.95 (s,3H), 3.11 (ddd, J=13.5, 12.0, 3.5 Hz, 2H), 2.62 (m, 1H), 2.06-2.01 (m,2H), 1.81-1.73 (m, 2H).

LCMS (ESI) Rt=2.04 minutes MS m/z 281 [M+H]⁺

Preparation 206 1-(3-methoxy-4-nitrophenyl)-4-methylpiperazine

The title compound was prepared according to the method described forPreparations 78 and 79 using 4-fluoro-2-methoxy-1-nitrobenzene and1-methylpiperazine. The residue was purified by silica gel columnchromatography eluting with 0-20% MeOH in EtOAc.

¹H NMR (500 MHz, MeOD): δ 7.95 (d, J=9.5 Hz, 1H), 6.58 (dd, J=9.5, 2.5Hz, 1H), 6.55 (d, J=2.5 Hz, 1H), 3.95 (s, 3H), 3.49-3.47 (m, 4H),2.61-2.59 (m, 4H), 2.37 (s, 3H).

LCMS (ESI) Rt=0.82 minutes MS m/z 252 [M+H]⁺

Preparation 207 4-(3-chloro-4-nitrophenyl)morpholine

The title compound was prepared according to the method described forPreparation 78 using 2-chloro-4-fluoro-1-nitrobenzene. The residue waspurified by silica gel column chromatography eluting with 0-50% EtOAc incyclohexane.

¹H NMR (500 MHz, CDCl₃): δ 8.05 (d, J=9.5 Hz, 1H), 6.89 (d, J=2.5 Hz,1H), 6.77 (dd, J=9.5, 2.5 Hz, 1H), 3.88-3.87 (m, 4H), 3.37-3.35 (m, 4H).

LCMS (ESI) Rt=2.31 minutes MS m/z 243 [M+H]⁺

Preparation 208 1-(3-methoxy-4-nitrophenyl)-4-(methylsulfonyl)piperazine

The title compound was prepared according to the method described forPreparation 78 using 4-fluoro-2-methoxy-1-nitrobenzene and1-(methylsulfonyl)piperazine for 96 hours. The residue was purified bysilica gel column chromatography eluting with 50-100% DCM incyclohexanes.

¹H NMR (500 MHz, CDCl₃): δ 8.02 (d, J=9.0 Hz, 1H), 6.54-6.50 (m, 2H),3.99 (s, 3H), 3.55-3.53 (m, 4H), 3.47-3.45 (m, 4H), 2.87 (s, 3H).

LCMS (ESI) Rt=1.82 minutes MS m/z 316 [M+H]⁺

Preparation 209 5-bromo-1-(2-methoxyethyl)-2-methyl-1H-imidazole

To a solution of 1-(2-methoxyethyl)-2-methyl-1H-imidazole (Preparation210, 0.5 g, 3.57 mmol) in THF (6.5 ml) was added potassium carbonate(0.1 g, 0.713 mmol) and NBS (0.6 g, 3.39 mmol). The reaction mixture wasstirred at r.t for 18 hrs. The reaction mixture was diluted with EtOAc(30 ml) and water (30 ml). The aqueous layer was re-extracted with EtOAc(30 ml). The combined organic layers were washed with brine (30 ml),dried (MgSO₄) and concentrated in vacuo to afford the title compound(500 mg, 64%).

1H NMR (500 MHz, MeOD) 6.86 (s, 1H), 4.16 (t, J=5.0 Hz, 2H), 3.63 (t,J=5.0 Hz, 2H), 3.31 (s, 3H), 2.42 (s, 3H).

LCMS (ESI) Rt=0.67 mins, MS m/z 219.13 [M+H]+;

Preparation 210 1-(2-methoxyethyl)-2-methyl-1H-imidazole

To a solution of 2-methyl-1H-imidazole (1.0 g, 12.2 mmol) and1-chloro-2-methoxyethane (1.34 ml, 14.62 mmol) in DMF (15 ml) was addedsodium hydride (0.49 g, 12.2 mmol). The reaction mixture was heated to80° C. for 18 hrs. The reaction mixture was transferred to a microwavevial and heated to 80° C. under microwave conditions for 1 hr. Thereaction mixture was diluted with DCM (40 ml) and aq. 2M Na2CO3 (30 ml)and water (40 ml). The aqueous layer was re-extracted with DCM severaltimes. The residue was purified by reverse phase chromatography (C18,100% water) to afford the title compound (1.13 g, 66%).

1H NMR (500 MHz, MeOD) 7.02 (d, J=1.5 Hz, 1H), 6.80 (d, J=1.5 Hz, 1H),4.09 (t, J=5.0 Hz, 2H), 3.64 (t, J=5.0 Hz, 2H), 3.31 (s, 3H), 2.36 (s,3H).

LCMS (ESI) Rt=0.47 mins, MS m/z 141.26 [M+H]+

Preparation 211(4-Amino-3-methoxyphenyl)(4-methylpiperazin-1-yl)methanone

HATU (1179 mg, 3.10 mmol) was added to a solution of4-amino-3-methoxybenzoic acid (461 mg, 2.76 mmol), DIPEA (1.24 mL, 7.12mmol) and 1-methylpiperazine (230 mg, 2.30 mmol) in DMF (12 mL) and thereaction mixture was stirred for 18 hours. The reaction was partitionedbetween EtOAc and water. The organic phase was washed with saturatedaqueous NaHCO₃ solution, water, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by elution through an SCX-2 column toafford the title compound as brown oil (179 mg, 31%).

¹H NMR (500 MHz, MeOD): δ 6.94 (dd, J=1.78, 8.62 Hz, 1H), 6.88 (ddd,J=1.78, 8.00, 8.62 Hz, 1H), 6.73 (dd, J=0.87, 8.00 Hz, 1H), 3.87 (s,3H), 3.72-3.60 (m, 4H), 3.08 (s, 3H), 2.50-2.42 (m, 4H).

LCMS (ESI) Rt=0.43 minutes MS m/z 250 [M+H]⁺

Preparation 2126-(2-(Methylthio)pyrido[3,4-d]pyrimidin-8-yl)-2-oxa-6-azaspiro[3.4]octane

The title compound was prepared according to the method described forPreparation 175 using 8-chloro-2-(methylthio)pyrido[3,4-d]pyrimidine(Preparation 33) and 2-oxa-6-azaspiro[3.4]octane hemioxalate salt. Theresidue was purified using silica gel column chromatography eluting with0-2% MeOH in EtOAc.

¹H NMR (500 MHz, CDCl₃): δ 8.98 (s, 1H), 8.05 (d, J=5.5 Hz, 1H), 6.78(d, J=5.5 Hz, 1H), 4.75 (d, J=6.1 Hz, 2H), 4.68 (d, J=6.1 Hz, 2H), 4.29(br, s, 2H), 4.1 (br s, 2H), 2.66 (s, 3H), 2.32 (t, J=6.9 Hz, 2H).

LCMS (ESI) Rt=1.32 minutes MS m/z 289 [M+H]⁺

Preparation 213 2-(Difluoromethoxy)-4-(1-methyl-1H-pyrazol-4-yl)aniline

The title compound was prepared according to the method described forPreparation 158 using4-(3-(difluoromethoxy)-4-nitrophenyl)-1-methyl-1H-pyrazole (Preparation214) in EtOH for 40 minutes. The residue was purified by elution throughan SCX-2 column using 50% methanol in chloroform followed by 50%chloroform in 7N NH₃/MeOH.

¹H NMR (500 MHz, CDCl₃): δ 7.66 (s, 1H), 7.5 (s, 1H), 7.15-7.13 (m, 2H),6.77 (d, J=8, Hz, 1H), 6.5 (t, J=74.3 Hz, 1H), 3.92 (s, 3H), 3.88 (br s,2H).

LCMS (ESI) R_(t)=2.07 minutes MS m/z 240 [M+H]⁺

Preparation 2144-(3-(Difluoromethoxy)-4-nitrophenyl)-1-methyl-1H-pyrazole

A suspension of 4-bromo-2-(difluoromethoxy)-1-nitrobenzene (Preparation215, 174 mg, 0.65 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(150 mg, 0.72 mmol), Pd(dppf)Cl₂.DCM (55 mg, 0.068 mmol), Na₂CO₃ (2M,0.65 mL, 1.3 mmol) in THF (4 mL) was stirred at 65° C. for 18 hours. Thereaction mixture was diluted with EtOAc and washed with water (10 mL),brine (10 mL) dried over sodium sulphate and concentrated in vacuo. Thecrude product was purified by silica gel column chromatography elutingwith 2% methanol in ethyl acetate to afford the title compound as awhite powder (140 mg, 80%).

¹H NMR (500 MHz, CDCl₃): δ 7.98 (d, J=8.5 Hz, 1H), 7.82 (s, 1H), 7.76(s, 1H), 7.44 (dd, J=8.5, 1.8 Hz, 1H), 7.41 (s, 1H), 6.67 (t, J=73.3 Hz,1H), 3.98 (s, 3H).

LCMS (ESI) Rt=2.38 minutes MS m/z 270 [M+H]⁺

Preparation 215 2-(Difluoromethoxy)-4-bromo-1-nitrobenzene

5-Bromo-2-nitrophenol (1 g, 4.59 mmol) and methyl2-chloro-2,2-difluoroacetate (991 mg, 6.9 mmol) were dissolved in dryDMF (3 mL). Potassium carbonate (1.27 g, 9.18 mmol) was added and thereaction was stirred at 120° C. for 1 hour. The reaction was cooled toroom temperature and diluted with ethyl acetate (20 mL). The organicsolution was washed with water (20 mL), brine (20 mL), dried over sodiumsulphate and concentrated in vacuo. The residue was purified by silicagel column chromatography eluting with 20% dichloromethane in hexanes toafford the title compound as a dark brown oil (375 mg, 30%).

¹H NMR (500 MHz, CDCl₃): δ 7.84 (d, J=8.7 Hz, 1H), 7.59-7.55 (m, 1H),7.54 (dd, J=8.7, 2 Hz, 1H), 6.65 (t, J=72.5 Hz, 1H).

LCMS (ESI) Rt=2.58 minutes

Preparation 216 2-Ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)aniline

The title compound was prepared according to the method described forPreparation 158 using3-(3-Ethoxy-4-nitrophenyl)-4-methyl-4H-1,2,4-triazole (Preparation 217)in EtOAc and EtOH (1:8 v:v).

¹H NMR (500 MHz, DMSO-d₆): δ 8.44 (s, 1H), 7.11 (d, J=1.89 Hz, 1H), 7.04(dd, J=1.89, 7.88 Hz, 1H), 6.73 d, J=7.88 Hz, 1H), 5.12 (s, 2H), 4.06(q, J=6.94 Hz, 2H), 3.69 (s, 3H), 1.36 (t, J=6.94 Hz, 3H).

Preparation 217 3-(3-Ethoxy-4-nitrophenyl)-4-methyl-4H-1,2,4-triazole

5-(3-Ethoxy-4-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-thiol(Preparation 218, 1.16 g 4.14 mmole) was stirred with dichloromethane(11.8 mL) and the suspension cooled in ice. A solution of 35% hydrogenperoxide (0.91 mL, 12.2 mmole) in acetic acid (6 mL) was added dropwiseand the reaction was stirred at room temperature for 70 minutes.Dichloromethane (50 mL) was added followed by 2M aqueous sodiumhydroxide (48 mL) to pH=7. The layers were separated, the aqueousextracted with more dichloromethane, the organic layers combined, driedover sodium sulphate and concentrated in vacuo. The residue was purifiedby silica gel column chromatography eluting with 5-10% EtOH in DCM toafford the title compound (607 mg, 60%).

¹H NMR (500 MHz, DMSO-d₆): δ 8.66 (s, 1H), 8.03 (d, J=8.51 Hz, 1H), 7.65(d, J=1.58 Hz, 1H), 7.47 (dd, J=1.58, 8.51 Hz, 1H), 4.31 (q, J=7.25 Hz,2H), 3.81 (s, 3H), 1.36 (t, J=6.94 Hz, 3H).

Preparation 2185-(3-Ethoxy-4-nitrophenyl)-4-methyl-4H-1,2,4-triazole-3-thiol

3-Ethoxy-4-nitrobenzohydrazide (Preparation 219, 1287 mg 5.72 mmole) wasstirred in THF (26 mL) and a solution of methyl isothiocyanate (422 mg5.78 mmole) in THF (5 mL) was added. Triethylamine (102 uL, 0.71 mmole)was added and the reaction was stirred at 20° C. for 22 hours. Thesolvent was evaporated and replaced with 1M sodium hydroxide solution(85 mL) and the reaction was stirred at 45° C. for 2.5 hours. Thereaction was filtered through Celite and the filtrate extracted withether (2×45 mL). The aqueous was acidified using conc. hydrochloric acidand extracted with ethyl acetate (2×50 mL). The combined ethyl acetateextracts were washed with water and with brine, dried over sodiumsulfate and concentrated in vacuo to afford the title compound (1.16 g,72%).

¹H NMR (500 MHz, DMSO-d₆): δ 14.11 (br s, 1H), 8.03 (d, J=8.51 Hz, 1H),7.66 (d, J=1.58 Hz, 1H), 7.44 (dd, J=1.89, 8.51 Hz, 1H), 4.29 (q, J=6.94Hz, 2H), 3.56 (s, 3H), 1.35 (t, J=6.94 Hz, 3H).

Preparation 219 3-Ethoxy-4-nitrobenzohydrazide

3-Ethoxy-4-nitrobenzoic acid (PCT Int Appl. 2008003958, 1.06 g 5.02mmole) was stirred with dry THF (10 mL) and triethylamine (0.86 mL, 6.1mmol) and the solution was cooled in an ice bath. Ethyl chloroformate(0.56 mL, 5.85 mmol) was added dropwise and the reaction was stirred inthe ice bath for 15 minutes. Hydrazine hydrate (1.27 mL, 26 mmol) wasadded in one portion and the reaction stirred in the ice bath for 5minutes and then at 20° C. for 1 hour. The reaction was concentrated invacuo, partitioned between EtOAc (100 mL) and saturated aqueous sodiumbicarbonate (15 mL). The organic layer was collected, washed with brine,dried over sodium sulfate and concentrated in vacuo to afford the titlecompound (1.07 g, 95%).

¹H NMR (500 MHz, DMSO-d₆): δ 10.05 (br s, 1H, NH), 7.92 (d, J=8.20 Hz,1H), 7.69 (d, J=1.89 Hz, 1H), 7.51 (dd, J=1.58, 8.51 Hz, 1H), 4.70 (brs, 2H, NH₂), 4.27 (q, J=6.94 Hz, 2H), 1.35 (t, J=6.94 Hz, 3H).

Preparation 2206-(2-(Methylsulfonyl)pyrido[3,4-d]pyrimidin-8-yl)-2-oxa-6-azaspiro[3.4]octane

The title compound was prepared according to the method described forPreparation 172 using6-(2-(Methylthio)pyrido[3,4-d]pyrimidin-8-yl)-2-oxa-6-azaspiro[3.4]octane(Preparation 212). The residue was purified using silica gel columnchromatography eluting with 0-5% MeOH in EtOAc.

¹H NMR (500 MHz, CDCl₃): δ 9.34 (s, 1H), 8.34 (d, J=5.4 Hz, 1H), 6.96(d, J=5.4 Hz, 1H), 4.78 (d, J=6.2 Hz, 2H), 4.69 (d, J=6.2 Hz, 2H), 4.25(br s, 4H), 3.4 (s, 3H), 2.39 (t, J=6.8 Hz, 2H)

LCMS (ESI) R_(t)=1.25 minutes MS m/z 321 [M+H]⁺

Preparation 221N-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)formamide

The title compound was prepared according to the methods described forPreparations

150, 216, 217, 218 and 219 using 3-methoxy-4-nitrobenzoic acid.

¹H NMR (500 MHz, DMSO-d₆): δ 9.89 (br. s, 1H), 8.56 (s, 1H), 8.37 (d,J=1.9 Hz, 1H), 8.35 (d, J=8.3 Hz, 1H), 7.39 (d, J=1.9 Hz, 1H), 7.30 (dd,J=8.3, 1.9 Hz, 1H), 3.94 (s, 3H), 3.76 (s, 3H).

LCMS (ESI) Rt=1.27 minutes MS m/z 233 [M+H]⁺

Preparation 222 (4-Bromo-1-methyl-1H-pyrazol-5-yl)methanol

To a solution of 4-bromo-1-methyl-1H-pyrazole-5-carbaldehyde (677 mg,3.58 mmol) in MeOH (8 mL) at 0° C., NaBH₄ (136 mg, 0.86 mmol) was added.The solution was stirred at room temperature for 2 hours. The reactionwas concentrated in vacuo and diluted with water. The solution wasextracted with EtOAc, the organic layer collected, dried over sodiumsulphate and concentrated in vacuo to afford the title compound as awhite solid (614 mg, 90%).

¹H NMR (500 MHz, CDCl₃): δ 7.43 (s, 1H), 4.72 (s, 2H), 3.97 (s, 3H),2.09 (s, 1H).

LCMS (ESI) Rt=1.29 minutes MS m/z 191 [M⁷⁹Br+H]⁺

The invention claimed is:
 1. A compound of formula Ic shown below:

wherein: R₁ is chloro, (1-6C)alkyl, (1-8C)heteroalkyl, aryl,aryl(1-2C)alkyl, heteroaryl, heteroaryl(1-2C)alkyl,heterocyclyl(1-2C)alkyl, (3-8C)cycloalkyl, (3-8C)cycloalkyl(1-2C)alkyl,NR₇R_(8,) OR_(9,) C(O)R_(9,) C(O)OR_(9,) OC(O)R_(9,) N(R₁₀)OR_(9,)N(R₁₀)C(O)OR_(9,) C(O)N(R₁₀)R_(9,) N(R₁₀)C(O)R_(9,) S(O)_(p)R₉ (where pis 0, 1 or 2), SO₂N(R₁₀)R_(9,) N(R₁₀)SO₂R_(9,) N(R₁₀)SOR₉ or SON(R₁₀)R₉;and wherein R₁ is optionally substituted by one or more substituentgroups selected from fluoro, chloro, trifluoromethyl, trifluoromethoxy,cyano, nitro, hydroxy, amino, carboxy, carbamoyl, sulphamoyl,(1-4C)alkyl, (1-4C)alkoxy, S(O)_(q)CH3 (where q is 0, 1 or 2),methylamino, dimethylamino, aryl, aryl(1-2C)alkyl, heteroaryl,heteroaryl(1-2C)alkyl, heterocyclyl, heterocyclyl(1-2C)alkyl,(3-8C)cycloalkyl, and (3-8C)cycloalkyl(1-2C)alkyl, and wherein any(1-4C)alkyl, (1-4C)alkoxy, aryl, heteroaryl, heterocyclyl, or(3-8C)cycloalkyl moiety present within a substituent group on R₁ isoptionally further substituted by fluoro, chloro, trifluoromethyl,trifluoromethoxy, cyano, nitro, hydroxy, amino, carboxy, carbamoyl,sulphamoyl, (1-4C)alkyl, NR_(a)R_(b), OR_(a), C(O)R_(a), C(O)OR_(a),OC(O)R_(a), N(R_(b))OR_(a), C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a),S(O)_(p)R_(a) (where p is 0, 1 or 2), SO₂N(R_(b))R_(a), orN(R_(b))SO₂R_(a), wherein R_(a) and R_(b) are each independently H or(1-4C)alkyl; R₃ is hydrogen, (1-4C)alkyl, (3-6C)cycloalkyl, halo, CF₃,CN or (1-4C)alkoxy; R₄ is hydrogen, (1-3C)alkyl, (1-3C)alkoxy, fluoro,chloro or CF₃; Ar has the formula:

wherein: (i) all of A₁, A₂ and A₃ are CH; or (ii) one of A₁, A₂ and A₃is N and the others are CH; R₅ is hydrogen, cyano, (1-3C)alkyl,(1-3C)fluoroalkyl, (1-3C)alkoxy, (1-3C)fluoroalkoxy, or halo, andwherein any alkyl or alkoxy moieties present within a R₅ substituentgroup are optionally further substituted by hydroxy or methoxy; R₆ ishalo, trifluoromethyl, trifluoromethoxy, cyano, nitro, hydroxy, amino,carboxy, carbamoyl, sulphamoyl, ureido, (1-6C)alkyl, (2-6C)alkenyl,(2-6C)alkynyl, or a group of the formula:-L¹-L²-R₁₇ wherein L¹ is absent; L² is absent or is O, S, SO, SO_(2,)N(R₂₀), C(O), C(O)O, OC(O), CH(OR₂₀), C(O)N(R₂₀), N(R₂₀)C(O),N(R₂₀)C(O)N(R₂₁), S(O)₂N(R₂₀), or N(R₂₁)SO₂, wherein R₂₀and R₂₁ are eachindependently hydrogen or (1-2C)alkyl; and R₁₇ is (1-6C)alkyl, aryl,aryl-(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl-(1-4C)alkyl,heteroaryl, heteroaryl-(1-4C)alkyl, heterocyclyl,heterocyclyl-(1-4C)alkyl, and wherein R₁₇ is optionally furthersubstituted by one or more substituent groups independently selectedfrom oxo, halo, cyano, nitro, hydroxy, NR₂₂R₂₃, (1-4C)alkoxy,(1-4C)alkyl, (3-8 C)cycloalkyl, (3-8C)cycloalkyl-(1-3 C)alkyl, (1-5C)alkanoyl, (1-5C)alkylsulphonyl, heterocyclyl,heterocyclyl-(1-2C)alkyl, heteroaryl, heteroaryl-(1-2C)alkyl, CONR₂₂R₂₃,and SO₂NR₂₂R₂₃; wherein R₂₂ and R₂₃ are each independently hydrogen,(1-4C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl; andwherein when said substituent group comprises an alkyl, cycloalkyl,heterocyclyl or heteroaryl moiety then said moiety is optionally furthersubstituted by hydroxy, fluoro, chloro, cyano, CF₃, OCF₃, (1-2C)alkyl,(1-2C)alkoxy, SO₂(1-2C)alkyl or NR_(e)R_(f) (where R_(e) and R_(f) areeach independently hydrogen, (1-3C)alkyl, (3-6C)cycloalkyl, or(3-6C)cycloalkyl(1-2C)alkyl); R₈ and R₉ are each independently hydrogen,(1-6C)alkyl, (1-6C)alkoxy, (3-9C)cycloalkyl,(3-9C)cycloalkyl-(1-2C)alkyl, aryl, aryl-(1-2C)alkyl, heterocyclyl,heterocyclyl-(1-2C)alkyl, heteroaryl, or heteroaryl-(1-2C)alkyl, andwherein R₈ and R₉ are optionally further substituted by one or moresubstituents selected from hydroxy, fluoro, chloro, cyano, CF₃, OCF₃(1-2C)alkyl and (1-2C)alkoxy; R₇ and R₁₀ are independently hydrogen,(1-6C)alkyl, (3-6C)cycloalkyl, or (3-6C)cycloalkyl-(1-2C)alkyl, andwherein R₇ and R₁₀ are optionally further substituted by one or moresubstituents selected from hydroxy, fluoro, chloro, cyano, CF₃, OCF₃,(1-2C)alkyl and (1-2C)alkoxy; subject to the proviso that: R₆ is notmethoxy when R₁ is S(O)₂R₉ and R₉ is heterocyclyl; or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1, wherein R₁is (1-6C)alkyl, phenyl, phenyl(1-2C)alkyl, 5 or 6 membered heteroaryl, 5or 6 membered heteroaryl(1-2C)alkyl, 3 to 9 memberedheterocyclyl(1-2C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl,NR₇R₈, OR₉, C(O)R₉, C(O)OR₉, OC(O)R₉, N(R₁₀)OR₉, N(R₁₀)C(O)OR₉,C(O)N(R₁₀)R₉, N(R₁₀)C(O)R₉, S(O)_(p)R₉ (where p is 0, 1 or 2),SO₂N(R₁₀)R₉, or N(R₁₀)SO₂R₉; and wherein R₁ is optionally substituted byone or more substituent groups selected from fluoro, chloro,trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, carbamoyl,sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(O)_(q)CH₃ (where q is 0, 1 or2), methylamino, dimethylamino, 5 or 6 membered heteroaryl, 5 or 6membered heteroaryl(1-2C)alkyl, 3 to 6 membered heterocyclyl, 3 to 6membered heterocyclyl(1-2C)alkyl, (3-6C)cycloalkyl, and(3-6C)cycloalkyl(1-2C)alkyl, and wherein any (1-4C)alkyl, (1-4C)alkoxy,heteroaryl, heterocyclyl, or (3-6C)cycloalkyl moiety present within asubstituent group on R₁ is optionally further substituted by fluoro,chloro, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino,carboxy, carbamoyl, sulphamoyl, (1-4C)alkyl, NR_(a)R_(b), OR_(a),C(O)R_(a), C(O)OR_(a), OC(O)R_(a), N(R_(b))OR_(a), C(O)N(R_(b))R_(a),N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is 0, 1 or 2),SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a), wherein R_(a) and R_(b) are eachindependently H or (1-4C)alkyl.
 3. A compound according to claim 2,wherein R₁ is (1-6C)alkyl, phenyl, phenyl(1-2C)alkyl, 5 or 6 memberedheteroaryl, 5 or 6 membered heteroaryl(1-2C)alkyl, 3 to 9 memberedheterocyclyl(1-2C)alkyl, (3-6C)cycloalkyl, (3-6C)cycloalkyl(1-2C)alkyl,NR₇R₈, OR₉, C(O)R₉, C(O)OR₉, OC(O)R₉, N(R₁₀)OR₉, N(R₁₀)C(O)OR₉,C(O)N(R₁₀)R₉, N(R₁₀)C(O)R₉, S(O)_(p)R₉ (where p is 0, 1 or 2),SO₂N(R₁₀)R₉, or N(R₁₀)SO₂R₉; and wherein R₁ is optionally substituted byone or more substituent groups selected from fluoro, chloro,trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino, carbamoyl,sulphamoyl, (1-4C)alkyl, (1-4C)alkoxy, S(O)_(q)CH₃ (where q is 0, 1 or2), methylamino or dimethylamino, 5 or 6 membered heteroaryl, and 4 to 6membered heterocyclyl, and wherein any (1-4C)alkyl, (1-4C)alkoxy,heteroaryl, or heterocyclyl moiety present within a substituent group onR₁ is optionally further substituted by fluoro, chloro, trifluoromethyl,trifluoromethoxy, cyano, hydroxy, amino, carbamoyl, sulphamoyl,(1-4C)alkyl, NR_(a)R_(b), OR_(a), C(O)R_(a), C(O)OR_(a), OC(O)R_(a),C(O)N(R_(b))R_(a), N(R_(b))C(O)R_(a), S(O)_(p)R_(a) (where p is 0, 1 or2), SO₂N(R_(b))R_(a), or N(R_(b))SO₂R_(a), wherein R_(a) and R_(b) areeach independently H or (1-4C)alkyl.
 4. A compound according to claim 1,wherein R₃ is hydrogen, (1-2C)alkyl, or (3-6C)cycloalkyl.
 5. A compoundaccording to claim 1, wherein R₄ is hydrogen, (1-2C)alkyl, (1-2C)alkoxy,fluoro, chloro or CF₃.
 6. A compound according to claim 1, wherein Arhas the formula:

wherein: (i) all of A₁, A₂ and A₃ are CH; or (ii) one of A₁, A₂ and A₃is N and the others are CH; R₅ is hydrogen, cyano, (1-3C)alkyl,(1-3C)perfluoroalkyl, (1-3C)alkoxy, (1-3C)fluoroalkoxy, or halo, andwherein any alkyl or alkoxy moieties present within a Rs substituentgroup are optionally further substituted by hydroxy or methoxy; and R₆is halo, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, amino,carboxy, carbamoyl, sulphamoyl, or a group of the formula:-L¹-L²-R₁₇ wherein L¹ is absent; L² is absent or is O, S, SO, SO₂,N(R₂₀), C(O), C(O)O, OC(O), CH(OR₂₀), C(O)N(R₂₀), N(R₂₀)C(O),N(R₂₀)C(O)N(R₂₁), S(O)₂N(R₂₀), or N(R₂₀)SO₂, wherein R₂₀ and R₂₁ areeach independently hydrogen or (1-2C)alkyl; and R₁₇ is (1-6C)alkyl,aryl, (3-6C)cycloalkyl, 5 or 6 membered heteroaryl, or 3 to 8 memberedheterocyclyl, and wherein R₁₇ is optionally further substituted by oneor more substituent groups independently selected from oxo, halo, cyano,nitro, hydroxy, NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl, (3-8C)cycloalkyl,(3-8C)cycloalkyl-(1-3C)alkyl, (1-5C)alkanoyl, (1-5C)alkylsulphonyl, 3 to6 membered heterocyclyl, 3 to 6 membered heterocyclyl-(1-2C)alkyl, 5 or6 membered heteroaryl, 5 or 6 membered heteroaryl-(1-2C)alkyl,CONR₂₂R_(23,) and SO₂NR₂₂R23; wherein R₂₂ and R₂₃ are each independentlyhydrogen, (1-4C)alkyl, (3-6C)cycloalkyl or (3-6C)cycloalkyl(1-2C)alkyl;or R₂₂ and R₂₃ can be linked such that, together with the nitrogen atomto which they are attached, they form a 4-6 membered heterocyclic ring;and wherein when said substituent group comprises an alkyl, cycloalkyl,heterocyclyl or heteroaryl moiety then said moiety is optionally furthersubstituted by hydroxy, fluoro, chloro, cyano, CF₃, OCF₃, (1-2C)alkyl,(1-2C)alkoxy, SO₂(1-2C)alkyl or NR_(e)R_(f) (where R_(e) and R_(f) areeach independently hydrogen, (1-3C)alkyl, (3-6C)cycloalkyl, or(3-6C)cycloalkyl(1-2C)alkyl).
 7. A compound according to claim 6,wherein Ar has the formula:

wherein: (i) all of A₁, A₂ and A₃ are CH; or (ii) A₃ is CH and one of A₁or A₂ is N and the other is CH; and R₅ and R₆ are each as defined inclaim
 6. 8. A compound according to claim 1, wherein R₅ is (1-2C)alkyl,CF₃, (1-2C)alkoxy, —OCF₃, —OCF₂H or Cl.
 9. A compound according to claim1, wherein R₆ is a group of the formula:-L¹-L²-R₁₇ wherein L¹ is absent; L² is absent or is O, S, SO, SO₂,N(R₂₀), C(O), C(O)O, OC(O), CH(OR₂₀), C(O)N(R₂₀), N(R₂₀)C(O),N(R₂₀)C(O)N(R₂₁), S(O)₂N(R₂₀), or N(R₂₀)SO₂, wherein R₂₀ and R₂₁ areeach independently selected from hydrogen or (1-2C)alkyl; and R₁₇ is(1-6C)alkyl, aryl, (3-6C)cycloalkyl, 5 or 6 membered heteroaryl, or 3 to8 membered heterocyclyl, and wherein R₁₇ is optionally furthersubstituted by one or more substituent groups independently selectedfrom oxo, halo, cyano, hydroxy, NR₂₂R₂₃, (1-4C)alkoxy, (1-4C)alkyl,(1-5C)alkylsulphonyl, 3 to 6 membered heterocyclyl, 3 to 6 memberedheterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, 5 or 6 memberedheteroaryl-(1-2C)alkyl, CONR₂₂R₂₃, and SO₂NR₂₂R₂₃; wherein R₂₂ and R₂₃are each independently hydrogen, (1-4C)alkyl or (3-6C)cycloalkyl or(3-6C)cycloalkyl(1-2C)alkyl; or R₂₂ and R₂₃ can be linked such that,together with the nitrogen atom to which they are attached, they form a4-6 membered heterocyclic ring; and wherein when said substituent groupcomprises an alkyl, cycloalkyl, heterocyclyl or heteroaryl moiety thensaid moiety is optionally further substituted by hydroxy, fluoro,chloro, cyano, CF₃, OCF₃, (1-2C)alkyl, (1-2C)alkoxy, SO₂(1-2C)alkyl orNR_(e)R_(f) (where R_(e) and R_(f) are each independently hydrogen or(1-2C)alkyl).
 10. A compound according to claim 1, wherein R₅ and R₉ areeach independently hydrogen, (1-6C)alkyl, (3-9C)cycloalkyl,(3-6C)cycloalkyl-(1-2C)alkyl, phenyl, 3 to 9 membered heterocyclyl, 3 to9 membered heterocyclyl-(1-2C)alkyl, 5 or 6 membered heteroaryl, or 5 or6 membered heteroaryl-(1-2C)alkyl, and wherein R₅ and R₉ are optionallyfurther substituted by one or more substituents selected from hydroxy,fluoro, chloro, cyano, CF₃, OCF₃, (1-2C)alkyl and (1-2C)alkoxy.
 11. Acompound according to claim 1, wherein R₇ and R₁₀ are independentlyhydrogen or (1-4C)alkyl.
 12. A compound according to claim 1, whereinsaid compound is any one of the following:(3-methoxy-4-((8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone;N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine;N-(2-chloro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine;N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-phenylpyrido[3,4-d]pyrimidin-2-amine;8-cyclopropyl-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine;N-(2-methoxy-5-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine;N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine;N8,N8-diethyl-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-cyclopentyl-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-cyclohexyl-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-(cyclopropylmethyl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;8-(1-methyl-1H-pyrazol-4-yl)-N-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine;N8-cyclopentyl-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-methylpyrido[3,4-d]pyrimidine-2,8-diamine;N-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine;N-(2-isopropoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine;N-(2-(2-methoxyethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-2-amine;N8-isopentyl-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-isobutyl-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;8-(cyclohexylthio)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine;N8-cyclohexyl-N2-(2-methoxy-4-(1-(2-(4-methylpiperazin-1-yl)ethyl)-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;8-(1-ethyl-1H-pyrazol-4-yl)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine;8-(1-isopropyl-1H-pyrazol-4-yl)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine;N8-cyclohexyl-N2-(4-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-(cyclopropylmethyl)-N2-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-cyclohexyl-N2-(2-methyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-(cyclopropylmethyl)-N2-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-(cyclohexylmethyl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;2-(4-(4-((8-(cyclohexylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)-1H-pyrazol-1-yl)ethanol;8-(cyclopropylmethoxy)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine;1-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)-2-methylpropan-2-ol;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(oxetan-3-ylmethyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-(3,3-dimethylbutan-2-yl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;3-((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)-2,2-dimethylpropan-1-ol;N2-(2-ethoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-6-morpholinopyridin-3-yl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-6-(methylsulfonyl)pyridin-3-yl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(1-methyl-1H-imidazol-5-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N8-(1-cyclopropylethyl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;2-(4-(3-methoxy-4-((8-((tetrahydro-2H-pyran-4-yl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)-1H-pyrazol-1-yl)ethanol;N2-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;(R)-N8-(3,3-dimethylbutan-2-yl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;(S)-N8-(3,3-dimethylbutan-2-yl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(tetrahydrofuran-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-((tetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;1-(2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyrrolidin-3-ol;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-methyl-N8-(tetrahydro-2H-pyran-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-(tert-butyl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(1-methylcyclohexyl)pyrido[3,4-d]pyrimidine-2,8-diamine;8-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidin-2-amine;N2-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-morpholinophenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N8-(2,2-difluoropropyl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-(3-methoxy-2,2-dimethylpropyl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(2,2,2-trifluoroethyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(2-oxa-6-azaspiro[3,4]octan-6-yl)pyrido[3,4-d]pyrimidin-2-amine;1-(((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)methyl)cyclobutanol;N2-(2-ethyl-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(4-(1-methyl-1H-pyrazol-4-yl)-2-(trifluoromethoxy)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-methylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8,N8-dimethylpyrido[3,4-d]pyrimidine-2,8-diamine;N-(2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)-2-methylpropane-2-sulfinamide;N2-(2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-((3-methyl oxetan-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(piperidin-1-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N-(2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)-2-methylpropane-2-sulfonamide;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(oxetan-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;(1-(3-methoxy-4-((8-(neopentylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)piperidin-4-yl)(morpholino)methanone;N2-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;1-(((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)methyl)cyclopropanol;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(1-methylpiperidin-4-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;2-((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)-2-methylpropan-1-ol;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(oxetan-2-ylmethyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-chloro-4-morpholinophenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamineN2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-((3-methyloxetan-3-y1)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-N8-(2-methoxy-2-methylpropyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;2-((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)ethanol;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(2-methoxyethyl)pyrido[3,4-d]pyrimidine-2,8-diamine;1-((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)propan-2-ol;2-((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)propan-1-ol;N2-(4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-((3-methyltetrahydrofuran-3-y1)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N8-((3-fluorooxetan-3-yl)methyl)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;2-((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)propane-1,3-diol;3-methoxy-2-((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)propan-1-ol;(3-(((2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)amino)methyl)oxetan-3-yl)methanol;(S)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N843-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;(R)-N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N843-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(1-(2-methoxyethyl)-2-methyl-1H-imidazol-5-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)-6-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-2-amine;N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-5-methylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-5-methyl-N8-neopentylpyrido[3,4-d]pyrimidine-2,8-diamine;(4-(3-methoxy-4-((8-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)-1-methyl-1H-pyrazol-5-yl)methanol;(4-(3-methoxy-4-((8-(((3-methyltetrahydrofuran-3-yl)methyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)-1-methyl-1H-pyrazol-5-yl)methanol;N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-4-(1-(2-methoxyethyl)-2-methyl-1H-imidazol-5-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(1-(2-methoxyethyl)-2-methyl-1H-imidazol-5-yl)phenyl)-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-ethoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-N8-((3-methyltetrahydrofuran-3-y1)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-6-(1-methyl-1H-tetrazol-5-yl)pyridin-3-y1)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(6-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxypyridin-3-yl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-4-(1-methyl-1H-tetrazol-5-yl)phenyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-8-(pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-2-amine;N2-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(1-(tetrahydrofuran-3-yl)ethyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-((3-methyltetrahydrofuran-3-y1)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-(2-methoxy-2-methylpropyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(6-(1,3-dimethyl-1H-pyrazol-4-yl)-2-methoxypyridin-3-yl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(6-(1,5-dimethyl-1H-pyrazol-4-yl)-2-methoxypyridin-3-yl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-6-(1-methyl-1H-1,2,3-triazol-5-yl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-6-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-3-yl)pyrido[3,4-d]pyrimidine-2,8-diamine;(3-methoxy-4-((8-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone;3-methoxy-4-((8-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)-N,N-dimethylbenzamide;(3-methoxy-4-((8-((2-methoxy-2-methylpropyl)amino)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)(4-methylpiperazin-1-yl)methanone;(1-(2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)pyrrolidin-3-yl)methanol;(1-(2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)piperidin-3-yl)methanol;(4-(2-((2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)amino)pyrido[3,4-d]pyrimidin-8-yl)morpholin-2-yl)methanol;N2-(2-(difluoromethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-(difluoromethoxy)-4-fluorophenyl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(4-(1-ethyl-1H-pyrazol-4-yl)-2-methoxyphenyl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;(3-methoxy-4-((8-(neopentylamino)pyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)(3-methoxyazetidin-1-yl)methanone;N2-(2-methoxy-4-(tetrahydro-2H-pyran-4-yl)phenyl)-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(4-chloro-2-(difluoromethoxy)phenyl)-N8-(2-methoxy-2-methylpropyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-5-methyl-N8-((3-methyloxetan-3-y1)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-methoxy-4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-5-methyl-N8-((3-methyltetrahydrofuran-3-yl)methyl)pyrido[3,4-d]pyrimidine-2,8-diamine;N8-(2-methoxy-2-methylpropyl)-N2-(2-methoxy-4-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;N2-(2-(difluoromethoxy)-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N8-(2-methoxy-2-methylpropyl)-6-methylpyrido[3,4-d]pyrimidine-2,8-diamine;or(4-(3-methoxy-4-((8-((2-methoxy-2-methylpropyl)amino)-6-methylpyrido[3,4-d]pyrimidin-2-yl)amino)phenyl)-1-methyl-1H-pyrazol-5-yl)methanol;or a pharmaceutically acceptable salt thereof.
 13. A pharmaceuticalcomposition comprising a compound according to claim 1, or apharmaceutically acceptable salt thereof, in admixture with apharmaceutically acceptable diluent or carrier.
 14. A pharmaceuticalcomposition comprising a compound according to claim 1, or apharmaceutically acceptable salt thereof, and another anti-tumor agent.15. A method of synthesizing a compound of the formula Ic, or apharmaceutically acceptable salt thereof, as claimed in claim 1, themethod comprising either: a) reacting a compound of formula A:

wherein R₁, R₃ and R₄ each as defined in claim 1, and LG_(A) is asuitable leaving group; with a compound of formula B:H₂N—Ar   Formula B wherein Ar is as defined in claim 1; or b) reacting acompound of formula C:

wherein R₁, R₃ and R₄ are as defined in claim 1; with a compound offormula B as defined in (a) above, or a compound of formula D:HC(O)HN—Ar   Formula D wherein Ar is as defined in claim 1; or a)reacting a compound of formula E:

wherein Ar, R₃ and R₄ are as defined in claim 1, and LG_(A) is asuitable leaving group as hereinbefore defined; with a compound offormula F:H₂N—R₁   Formula F wherein R₁ is as defined in claim 1; and optionallythereafter, and if necessary: i) removing any protecting groups present;ii) converting the compound formula Ic into another compound of formulaIc; and/or iii) forming a pharmaceutically acceptable salt thereof.